EGFR degrader and preparation method therefor and use thereof

Abstract

A bifunctional chimera heterocyclic compound represented by formula (I) and targeting epidermal growth factor receptor (EGFR), and a pharmaceutical composition thereof, a preparation method therefor, and a use thereof. The compound recruits a ubiquitin ligase to EGFR, thereby promoting ubiquitination of EGFR and proteasomal degradation of EGFR. Research results show that the compounds exhibit good EGFR degradation activity and can be used for treating EGFR-mediated diseases.

Description

An EGFR degrading agent, its preparation method and uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a novel bifunctional compound or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, deuterated compounds that can degrade EGFR, as well as pharmaceutical compositions, preparation methods and uses thereof. Background Technology

[0002] Cancer is one of the leading diseases threatening human life and health. With the development of targeted therapies, progress has been made in cancer treatment. For example, small-molecule inhibitors targeting the epidermal growth factor receptor (EGFR) selectively block the binding of EGFR to ATP, thereby inhibiting EGFR activation and downstream signaling pathways, leading to arrest of cell growth, proliferation, and metastasis, and ultimately apoptosis, achieving effective EGFR-mediated tumor control. Unfortunately, acquired resistance easily develops after the clinical use of EGFR inhibitors, primarily due to point mutations in EGFR that prevent small molecules from effectively binding, resulting in decreased or even absent inhibitory effects, such as the most common T790M mutation. To address this, researchers have gradually developed new-generation inhibitors that can effectively overcome the resistance problems of previous generations. Currently, third-generation EGFR inhibitors (such as osimertinib and amitinib) can effectively overcome the T790M mutation and have weaker activity against wild-type EGFR, reducing the toxic side effects of second-generation drugs. However, resistance to osimertinib has emerged (Nature Medicine, 2015, 21, 560-562). The main mechanism is a mutation at position 797 of EGFR, where a cysteine ​​residue is replaced by a serine residue (C797S), leading to the loss of the covalent bond between the cysteine ​​residue and the inhibitor, thus resulting in resistance. Therefore, developing fourth-generation EGFR therapeutics that can overcome the C797S mutation is of great significance and clinical value.

[0003] PROTAC (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can be recognized by the cell's proteasome, causing the degradation of the target protein and effectively reducing its concentration in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. In recent years, a number of patents (WO2019149922A1, WO2021127561A1, WO2022194269A1, WO2022012622A1, WO2022228547A, etc.) have reported a series of PROTAC-type compounds that can overcome the resistance problem of C797S by degrading EGFR protein, becoming a new research direction. Among them, HSK40118 from Sichuan Hisun Pharmaceutical Co., Ltd., HJ-002-03 from Hejing Pharmaceutical Technology (Shanghai) Co., Ltd., CFT8919 from C4 Company, and BG-60366 from BeiGene, all EGFR-PROTAC bifunctional molecules, have been approved for clinical trials.

[0004] While some progress has been made in EGFR allosteric inhibitors and EGFR degraders, the clinical demand for treating EGFR protein-related diseases still remains unmet. Therefore, developing novel PROTAC drugs that bind to EGFR protein and E3 ubiquitin ligases for the treatment of EGFR protein-related diseases holds great promise. Summary of the Invention

[0005] The purpose of this invention is to provide a novel bifunctional compound that can inhibit and degrade EGFR, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, deuterated compounds, pharmaceutical compositions thereof, preparation methods thereof, and uses for treating EGFR-related diseases.

[0006] The first aspect of this invention provides a compound of formula (Ⅰ), or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, or deuterated thereof:

[0007] in,

[0008] X is CR X Or N; R X Selected from hydrogen, halogen or C 1-3 alkyl;

[0009] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6cycloalkyl, C 1-6 alkoxy or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl or heteroaryl group is optionally surrounded by one or more carbon atoms. 1-6 Alkyl, C 1-6 Alkyl or halogen atom substitution;

[0010] R 1 R 2 Each is selected independently from: C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl group or cycloalkyl group is optionally substituted with 1-5 deuterium or halogen atoms;

[0011] R 3 Selected from: hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 The alkoxy group may optionally be replaced by one or more halogens;

[0012] R 4 Selected from: hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl-O-, the C 1-6 Alkyl, C 1- 6-alkoxy or C 3-7 The cycloalkyl-O- is optionally substituted with one or more halogens;

[0013] R 5 Selected from: hydrogen, deuterium, halogen, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the amino, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, phenyl, or heteroaryl group is optionally surrounded by 1-4 deuterium, halogen, hydroxyl, cyano, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)- or C 3-6 Cycloalkyl substitution, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms independently selected from O, S, or N; or R 5 Selected from: hydrogen, deuterium, halogen, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7Cycloalkyl, 3-8-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the amino, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, phenyl, or heteroaryl group is optionally surrounded by 1-4 deuterium, halogen, hydroxyl, cyano, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 2-6 alkenyl-C(O)-, or C 3-6 Cycloalkyl substitution, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms independently selected from O, S, or N;

[0014] L represents the connecting chain, selected from -L1-L2-L3-L4-L5, where...

[0015] L1 is selected from 3-12 membered heterocyclic groups or C 3-10 Cycloalkyl groups, wherein the heterocyclic or cycloalkyl group is optionally surrounded by 1 to 4 deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen or C. 1-6 alkyl;

[0016] L2, L3, L4, and L5 are independently selected from bonds, C, and C, respectively. 1-6 Alkylene, 3-12 membered heterocyclic group, C 3-12 cycloalkyl, C 2-6 imidene group, C 2-6 Ethyne group, -C(O)-, -C(O)-N(R) L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein, the C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally each independently bound by one or more R groups. L3 Replace; the C 1-6 Alkylene, C 2-6 imide and C 2-6 The ethynyl group is optionally and independently controlled by one or more R groups. L4 replace;

[0017] R L2 Selected from hydrogen or C 1-6 alkyl;

[0018] Each R L3 Each is independently selected from oxo, hydroxyl, and -OC groups. 1-6Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Haloalkyl or 3-12 membered heterocyclic groups;

[0019] Each R L4 Each is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 cycloalkyl or -OC 1-6 Alkyl; wherein, the C 1-6 Alkyl, C 3-8 cycloalkyl or -OC 1-6 Alkyl groups may be optionally substituted with 1-3 F atoms;

[0020] LBM is a group that binds to ubiquitin ligases.

[0021] In some embodiments of the present invention,

[0022] X is CR X Or N; R X Selected from hydrogen, halogen or C 1-3 alkyl;

[0023] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl or heteroaryl group is optionally surrounded by one or more carbon atoms. 1-6 Alkyl, C 1-6 Alkyl or halogen atom substitution;

[0024] R 1 R 2 Each is selected independently from: C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl group or cycloalkyl group is optionally substituted with 1-5 deuterium or halogen atoms;

[0025] R 3 Selected from: hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 The alkoxy group may optionally be replaced by one or more halogens;

[0026] R4 Selected from: hydrogen, deuterium, halogens, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 The alkoxy group may optionally be replaced by one or more halogens;

[0027] R 5 Selected from: hydrogen, deuterium, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, phenyl, or heteroaryl group is optionally surrounded by 1-4 deuterium, halogen, hydroxyl, cyano, or C groups. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl substitution, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms independently selected from O, S, or N;

[0028] L represents the connecting chain, selected from -L1-L2-L3-L4-L5, where...

[0029] L1 is selected from 3-12 membered heterocyclic groups or C 3-10 Cycloalkyl groups, wherein the heterocyclic or cycloalkyl group is optionally surrounded by 1 to 4 deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen or C. 1-6 alkyl;

[0030] L2, L3, L4, and L5 are independently selected from bonds, C, and C, respectively. 1-6 Alkylene, 3-12 membered heterocyclic group, C 3-12 cycloalkyl, C 2-6 imidene group, C 2-6 Ethyne group, -C(O)-, -C(O)-N(R) L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein, the C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally each independently bound by one or more R groups. L3 Replace; the C 1-6 Alkylene, C 2-6imide and C 2-6 The ethynyl group is optionally and independently controlled by one or more R groups. L4 replace;

[0031] R L2 Selected from hydrogen or C 1-6 alkyl;

[0032] Each R L3 Each is independently selected from oxo, hydroxyl, and -OC groups. 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Haloalkyl or 3-12 membered heterocyclic groups;

[0033] Each R L4 Each is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 cycloalkyl or -OC 1-6 Alkyl; wherein, the C 1-6 Alkyl, C 3-8 cycloalkyl or -OC 1-6 Alkyl groups may be optionally substituted with 1-3 F atoms;

[0034] LBM is a group that binds to ubiquitin ligases.

[0035] In some embodiments of the present invention,

[0036] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl or ethyl.

[0037] In some embodiments of the present invention,

[0038] X is CH.

[0039] In some embodiments of the present invention,

[0040] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z It is selected from hydrogen, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, -CF3-, -CHF2-, cyano or cyclopropyl.

[0041] In some embodiments of the present invention,

[0042] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R ZSelected from hydrogen, F, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl.

[0043] In some embodiments of the present invention,

[0044] R 1 R 2 Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0045] In some embodiments of the present invention,

[0046] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl or cyclopropyl; preferably: Br.

[0047] In some embodiments of the present invention,

[0048] R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or CF3CH2-O-; preferably: methoxy or CF3CH2-O-.

[0049] In some embodiments of the present invention,

[0050] R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, cyclopropyloxy, or cyclobutyloxy; preferably: methoxy.

[0051] In some embodiments of the present invention,

[0052] R 4 Selected from: hydrogen, methoxy, ethoxy, or isopropoxy; preferably: methoxy.

[0053] In some embodiments of the present invention,

[0054] R 5 Selected from: hydrogen, methyl, ethyl, vinyl, isopropyl, cyclopropyl, vinyl carbonylamino (CH2=CH2-CONH-), or Preferred: Ethyl or

[0055] In some embodiments of the present invention,

[0056] R 5 Selected from: hydrogen, nitro, CH3C(O)-NH-, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred:

[0057] In some embodiments of the present invention,

[0058] R5 Selected from: hydrogen, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred: Ethyl or

[0059] In some embodiments of the present invention,

[0060] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably: X is CH;

[0061] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, F, Cl, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl;

[0062] R 1 R 2 Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0063] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br;

[0064] R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, cyclopropyloxy, or cyclobutyloxy; preferably: methoxy;

[0065] R 5 Selected from: hydrogen, nitro, CH3C(O)-NH-, methyl, ethyl, vinyl, isopropyl, cyclopropyl, vinyl carbonylamino (CH2=CH2-CONH-), or Preferred: Ethyl or

[0066] In some embodiments of the present invention,

[0067] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably: X is CH;

[0068] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, F, Cl, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl;

[0069] R 1 R 2Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0070] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br;

[0071] R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, cyclopropyloxy, or cyclobutyloxy; preferably: methoxy;

[0072] R 5 Selected from: hydrogen, nitro, CH3C(O)-NH-, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred:

[0073] In some embodiments of the present invention,

[0074] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably: X is CH;

[0075] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen or methyl;

[0076] R 1 R 2 Each is independently selected from: hydrogen, methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0077] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br;

[0078] R 4 Selected from: hydrogen, methoxy, ethoxy, or isopropoxy; preferably: methoxy;

[0079] R 5 Selected from: hydrogen, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred:

[0080] In some embodiments of the present invention,

[0081] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably: X is CH;

[0082] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, F, Cl, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl;

[0083] R 1 R 2 Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0084] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br;

[0085] R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or CF3CH2-O-; preferably: methoxy or CF3CH2-O-;

[0086] R 5 Selected from: hydrogen, nitro, CH3C(O)-NH-, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred: Ethyl or

[0087] In some embodiments of the present invention,

[0088] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably: X is CH;

[0089] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, F, Cl, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl;

[0090] R 1 R 2 Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0091] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br;

[0092] R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, or CF3CH2-O-; preferably: methoxy or CF3CH2-O-;

[0093] R 5Selected from: hydrogen, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred: Ethyl or

[0094] In some embodiments of the present invention,

[0095] X is CR X Or N; R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably: X is CH;

[0096] Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, F, Cl, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl;

[0097] R 1 R 2 Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl;

[0098] R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br;

[0099] R 4 Selected from: hydrogen, methoxy, ethoxy, or isopropoxy; preferably: methoxy;

[0100] R 5 Selected from: hydrogen, methyl, ethyl, vinyl, isopropyl, cyclopropyl or Preferred:

[0101] In some embodiments of the present invention, the LBM is selected from:

[0102] Each of W1, W2, and W is independently selected from: C(R) b ) or N, the R b Selected from hydrogen or C 1-6 alkyl;

[0103] Indicates a single bond or a double bond;

[0104] X1 and Z1 are independently selected from CH or N, and Y1 is selected from CH, N or CO;

[0105] X2 is selected from: CH2 or C=O;

[0106] X3 is selected from: CH or N;

[0107] Y2 is selected from: non-existent, or NRe R e Selected from H or C 1-4 alkyl;

[0108] R a1 R a2 Each is independently selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl;

[0109] R c1 Selected from hydrogen, C 1-6 Alkyl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more deuterium, halogen, amino, hydroxyl, carboxyl, or cyano groups;

[0110] R d Selected from hydrogen, halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OC 1-4 alkyl;

[0111] R d1 Selected from hydrogen or halogen.

[0112] In some embodiments of the present invention, in formula (B-1),

[0113] R c1 Selected from hydrogen, deuterium, methyl, ethyl or isopropyl, wherein the methyl, ethyl or isopropyl group is optionally substituted with one or more deuterium groups; preferably: hydrogen, deuterium, methyl or CD3.

[0114] In some embodiments of the present invention, the LBM is selected from:

[0115] In some embodiments of the present invention, the LBM is selected from:

[0116] In some embodiments of the present invention, L is selected from -L1-L2-L3-L4-L5, wherein,

[0117] L1 is selected from 4-7 membered monoheterocyclic groups or 7-11 membered heterospirocyclic groups, wherein the monoheterocyclic or heterospirocyclic group is optionally surrounded by one to four deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen, deuterium, or C. 1-3 alkyl;

[0118] L2, L3, L4, and L5 are independently selected from: key, C 1-6 Alkylene, 4-7 membered monoheterocyclic group, 7-11 membered heterospirocyclic group, 7-9 membered heterobridged cyclic group, C 4-7 cycloalkyl, C 2-6 imidene group, C 2-4 Ethyne group, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R) L2 - or -N(R) L2 -; wherein the monoheterocyclic group, heterospirocyclic group, or heterobridged cyclic group is optionally surrounded by a hydroxyl group, C 1-3 Alkyl or C 1-3 Alkoxy substitution; R L2 Selected from hydrogen or C 1-3 Alkyl groups, wherein the alkyl groups are optionally substituted with 1 to 7 deuterium atoms.

[0119] In some embodiments of the present invention, L is selected from -L1-L2-L3-L4-L5, wherein,

[0120] L1 is selected from 5-6 member monoheterocyclic groups or 7-11 member heterospirocyclic groups, wherein the monoheterocyclic or heterospirocyclic group is optionally surrounded by one to four deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen, deuterium, or C. 1-3 alkyl;

[0121] L2, L3, L4, and L5 are independently selected from: key, C 1-6 Alkylene, 4-6 membered monoheterocyclic group, 7-11 membered heterospirocyclic group, 7-9 membered heterobridged cyclic group, C 4-6 cycloalkyl, C 2-4 Ethyne group, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R) L2 - or -N(R) L2 -; wherein the monoheterocyclic group, heterospirocyclic group, or heterobridged cyclic group is optionally surrounded by a hydroxyl group, C 1-3 Alkyl or C 1-3 Alkoxy substitution; R L2 It is selected from hydrogen, methyl or ethyl, wherein the methyl or ethyl group is optionally substituted with 1 to 5 deuterium atoms.

[0122] In some embodiments of the present invention, L is selected from -L1-L2-L3-L4-L5, wherein,

[0123] L1 is selected from 4-7 membered monoheterocyclic groups or 7-11 membered heterospirocyclic groups, wherein the monoheterocyclic or heterospirocyclic group is optionally surrounded by one to four deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen, deuterium, or C. 1-3 alkyl;

[0124] L2, L3, L4, and L5 are independently selected from: key, C 1-6 Alkylene, 4-7 membered monoheterocyclic group, 7-11 membered heterospirocyclic group, C 4-7 cycloalkyl, C 2-6 imidene group, C 2-4 Ethyne group, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R) L2 - or -N(R) L2 )-; wherein the monoheterocyclic or heterospirocyclic group is optionally replaced by a hydroxyl group, C 1-3 Alkyl or C 1-3 Alkoxy substitution; R L2 Selected from hydrogen or C 1-3 Alkyl groups, wherein the alkyl groups are optionally substituted with 1 to 7 deuterium atoms.

[0125] In some embodiments of the present invention, L is selected from -L1-L2-L3-L4-L5, wherein,

[0126] L1 is selected from a 6-membered monoheterocyclic group or a 7-11-membered heterospirocyclic group, wherein the monoheterocyclic or heterospirocyclic group is optionally surrounded by one to four deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen, deuterium, or C. 1-3 alkyl;

[0127] L2, L3, L4, and L5 are independently selected from: key, C 1-6 Alkylene, 4-6 membered monoheterocyclic group, 7-11 membered heterospirocyclic group, C 4-6 cycloalkyl, C 2-4 Ethyne group, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R) L2 - or -N(R) L2 )-; wherein the monoheterocyclic or heterospirocyclic group is optionally replaced by a hydroxyl group, C 1-3 Alkyl or C 1-3 Alkoxy substitution; RL2 It is selected from hydrogen, methyl or ethyl, wherein the methyl or ethyl group is optionally substituted with 1 to 5 deuterium atoms.

[0128] In some embodiments of the present invention, L is selected from -L1-L2-L3-L4-L5-, wherein,

[0129] L1-L2 are selected from:

[0130] L2, L3, L4 and L5 are each independently selected from: bond, methylene, ethylene, piperidine, piperazine, ethynylene, 1-propynylene, 1-butynylene, -C(O)-, -C(O)-NH-, -C(O)-NCH3-, -NH-, -NCH3-, -NCD3- or 2,5-diazabicyclo[2.2.1]heptane; wherein the piperidine, piperazine or 2,5-diazabicyclo[2.2.1]heptane is optionally substituted with hydroxyl, methoxy or ethoxy.

[0131] In some embodiments of the present invention, the L-LBM is selected from:

[0132] In some embodiments of the present invention, the L-LBM is selected from:

[0133] In some embodiments of the present invention, the compound of formula (I) is as follows:

[0134] Among them, X, Z1, Z2, Z3, Z4, R 1 R 2 R 3 R 4 R 5 L and LBM are as described in the compound of formula (I) above;

[0135] The preferred L-LBM is:

[0136] The preferred LBM is:

[0137] In some embodiments of the present invention, the compound of formula (I) is a compound of formula (I-2), (I-3), (I-4), or (I-5):

[0138] Among them, X, Z1, Z2, Z3, Z4, R 1 R 2 R 3 R4 R 5 R c1 As described in compound (I) above.

[0139] The above-mentioned preferred embodiments of the present invention can be combined arbitrarily.

[0140] Secondly, the present invention provides compounds having the following structures, and their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, and deuterated derivatives:

[0141] Table 1

[0142] Thirdly, the present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, deuterated compound thereof, and optionally a pharmaceutically acceptable carrier.

[0143] Fourthly, the object of the present invention also includes the use of the compounds shown in the present invention, or stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, deuterated compounds, and pharmaceutical compositions described in the present invention, in the preparation of medicaments for treating EGFR-mediated diseases.

[0144] The object of the present invention also includes providing the use of the compounds shown in the present invention, or stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, and deuterated compounds thereof, in the preparation of medicaments for treating cancer, preferably EGFR-mediated cancer.

[0145] The object of the present invention also includes the use of the compound shown in the present invention, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterated derivatives, in the preparation of a medicament for treating lung cancer, preferably EGFR-mediated lung cancer; wherein the lung cancer is preferably non-small cell lung cancer.

[0146] Fifthly, the object of the present invention also includes providing a method for degrading and / or inhibiting EGFR protein kinase in a patient or biological sample, comprising administering the patient or contacting the biological sample with the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, deuterates or pharmaceutical compositions of the present invention.

[0147] Sixthly, the object of the present invention also includes providing the use of the compound shown in the present invention, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterated derivatives, in the preparation of a medicament for treating cancer, preferably EGFR-mediated diseases, optionally in combination with other medicaments.

[0148] In a seventh aspect, the object of the present invention also includes providing a method for preventing and / or treating EGFR-mediated diseases, comprising administering to a patient a therapeutically effective dose of the compound shown in the present invention, or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, deuterated compound, or pharmaceutical composition described in the present invention.

[0149] This invention also provides the following general preparation methods for the compounds of this invention:

[0150] Synthesis Scheme 1

[0151] i) Compound I-a1 undergoes a chemical transformation to yield compound I-a2;

[0152] For example, compound I-a2 is obtained by using compounds I-a1 and NIS as basic raw materials;

[0153] ii) Compound I-a2 undergoes a chemical transformation to yield compound I-a3;

[0154] For example, compounds I-a2 and R 1 R 2 Using substituted phosphine oxide reagents and other similar raw materials, compound I-a3 was obtained;

[0155] iii) Compound I-a3 undergoes a chemical transformation to yield compound I-a4;

[0156] For example, compounds I-a3 and R 3 Using substituted 2,4-dichloropyrimidine and other similar raw materials, compound I-a4 was obtained;

[0157] iv) Compound I-b1 and the linker moiety L undergo a chemical transformation to yield compound I-b2;

[0158] For example, using compound I-b1 and linker L as basic raw materials, compound I-b2 can be obtained through a substitution reaction;

[0159] v) Compound I-b2 undergoes a chemical transformation to yield compound I-b3;

[0160] For example, using compound I-b2 and ligase-binding moieties as basic raw materials, compound I-b3 is obtained through reactions such as condensation and reductive amination.

[0161] vi) Compound I-b3 undergoes a chemical transformation to yield compound I-b4;

[0162] For example, compound I-b4 can be obtained by using compound I-b3 and reduced iron powder as basic raw materials through a reduction reaction;

[0163] vii) Compounds I-b4 and I-a4 undergo chemical transformation to yield compound I of general formula;

[0164] For example, using compounds I-b4 and I-a4 as basic raw materials, compound I of general formula can be obtained through substitution reaction.

[0165] Terminology Explanation

[0166] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0167] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1 to 20 carbon atoms, such as "C". 1-12 Alkyl", C 1-10 Alkyl", C 1-8 Alkyl", C 1-6 Alkyl", C 1-3 "Alkyl" refers to a group that is alkyl, and the number of carbon atoms in the carbon chain is between 1-10, 1-6, and 1-3. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, and n-octyl.

[0168] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic saturated or partially saturated aliphatic hydrocarbon group having a specific number of carbon atoms. Unless otherwise specified, this application includes all possible monocyclic and fused rings (including fused in fused, spiro, or bridged forms), including C 3-15 Cycloalkyl (3-15 membered cycloalkyl), preferably C 3-12 Cycloalkyl (3-12 membered cycloalkyl), preferably C 3-11 Cycloalkyl (3-11 membered cycloalkyl), further preferably C 3-9 Cycloalkyl (3-9 membered cycloalkyl), with C being more preferred. 3-8 Cycloalkyl (3-8 membered cycloalkyl), with C being even more preferred. 3-7 Cycloalkyl (3-7 membered cycloalkyl), with C being the most preferred. 3-6 Cycloalkyl (3-6 membered cycloalkyl); preferably C 4-12 Cycloalkyl (4-12 membered cycloalkyl), preferably C4-8 Cycloalkyl (4-8 membered cycloalkyl), with C being more preferred. 5-7 Cycloalkyl (5-7 membered cycloalkyl), or C 4-6 Cycloalkyl (4-6 membered cycloalkyl). Monocyclic cycloalkyl usually refers to C1 preferred. 3-12 Monocyclic alkyl (3-12 membered monocyclic alkyl), more preferably C 3-10 Monocyclic alkyl (3-10 membered monocyclic alkyl), further preferably C 3-8 Monocycloalkyl (3-8 membered monocycloalkyl), C 3-7 Monocycloalkyl (3-7 membered monocycloalkyl), C 4-7 Monocycloalkyl (4-7 membered monocycloalkyl), C 3-6 Monocyclic alkyl groups (3-6 membered monocyclic alkyl groups), examples of which include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. Fused-ring cycloalkyl groups include spirocyclic alkyl groups, fused-ring alkyl groups, and bridged-ring alkyl groups. Spirocyclic alkyl groups can be 7-12 membered spirocyclic alkyl groups, preferably 7-11 membered spirocyclic alkyl groups, and more preferably 7-9 membered spirocyclic alkyl groups, examples of which include, but are not limited to: The cycloalkyl group can be a 6-11 membered cycloalkyl group, preferably a 7-10 membered cycloalkyl group, more preferably an 8-10 membered cycloalkyl group, and even more preferably a 9-10 membered cycloalkyl group. Representative examples include, but are not limited to, cycloalkyl groups. Preferred examples of partially saturated cycloalkyl groups include, but are not limited to, those that are not cycloalkyl groups. Bridged cycloalkyl groups can be 6-10-membered bridged cycloalkyl groups, preferably 7-10-membered bridged cycloalkyl groups, examples of which include, but are not limited to:

[0169] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially saturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and one or more ring heteroatoms, comprising 3-20 ring atoms ("3-20 membered heterocyclic group"), wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, and the number of heteroatoms is preferably 1-5 (i.e. 1, 2, 3, 4 or 5), more preferably 1-4, further preferably 1-3, and even more preferably 1-2. Preferably, it contains 3-14 ring atoms (“3-14-membered heterocyclic group”), more preferably 3-12 ring atoms (“3-12-membered heterocyclic group”), more preferably 4-11 ring atoms (“4-11-membered heterocyclic group”), or more preferably 3-8 ring atoms (“3-8-membered heterocyclic group”), even more preferably 4-7 ring atoms (“4-7-membered heterocyclic group”), even more preferably 5-10 ring atoms (“5-10-membered heterocyclic group”), even more preferably 5-6 ring atoms (“5-6-membered heterocyclic group”); the number of heteroatoms is preferably 1, 2 or 3. The "heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group" or "monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "hetero-fused heterocyclic group"), bridged ("hetero-bridged heterocyclic group" or "bridged-ring heterocyclic group") or helical-fused ("hetero-spiral heterocyclic group" or "spiral-ring heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. The monocyclic group includes saturated or partially saturated monocyclic groups, comprising 3-9 quinary monocyclic groups, preferably 3-7 quinary monocyclic groups, more preferably 4-7 quinary monocyclic groups, further preferably 4-6 quinary monocyclic groups, even more preferably 5-6 quinary monocyclic groups, and still more preferably 6 quinary monocyclic groups. The heterospirocyclic group comprises a saturated or partially saturated heterospirocyclic group, comprising 7-11 membered heterospirocyclic groups, preferably 7-9 membered heterospirocyclic groups, more preferably 7-8 membered heterospirocyclic groups, and even more preferably 7 membered heterospirocyclic groups. The heterobridged cyclic group comprises a saturated or partially saturated heterobridged cyclic group, preferably 7-9 membered heterobridged cyclic group, more preferably 7-8 membered heterobridged cyclic group, and even more preferably 7 membered heterobridged cyclic group. The heterocyclic bicyclic system may include one or more heteroatoms in one or both rings. "Hypercyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic or heteroaryl groups, or a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an “unsubstituted heterocyclic group”) or substituted with one or more substituents (an “substituted heterocyclic group”).

[0170] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclopropane, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azircyclobutane, oxiranyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, pyrroliyl, dihydropyrroliyl, and pyrroliyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, imidazoalkyl, dioxopentyl, oxathiocyclopentyl, dithiocyclopentyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazine, morpholinyl, dithiocyclohexyl, and dioxazinanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazineyl, thiadiazineyl, oxathiazineyl, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazineyl, and thiocycloheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazineyl, and thiocycloheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Exemplary heterobridged cyclic structures include, but are not limited to, the following structures: Exemplary structures of heterospirocyclic groups include, but are not limited to, the following structures:

[0171] Unless otherwise specified, the terms "aryl" or "arylcyclol" indicate a group containing 6-16 carbon atoms (C64-C64). 6-16 Aryl or 6-16 aryl), or 6-14 carbon atoms (C 6-14 Aryl or 6-14 aryl), or 6-12 carbon atoms (C 6-12 Aryl or 6-12 aryl), or 6-10 carbon atoms (C 6-10 aryl or 6-10 aryl) or 6-8 carbon atoms (C6-8 Aromatic carbocyclic systems consisting of monocyclic, bicyclic, and tricyclic aryl groups (or 6-8-membered aryl groups). The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene, etc.

[0172] Unless otherwise specified, the term "heteroaryl" or "heteroarylcycloyl" refers to an aromatic monocyclic or polycyclic system containing a 5-14 member structure (5-14-membered heteroaryl), or a 5-12 member structure (5-12-membered heteroaryl), or a 5-10 member structure (or 5-10-membered heteroaryl), preferably a 5-8 member structure (5-8-membered heteroaryl), more preferably a 5-6 member structure (5-6-membered heteroaryl), wherein at least one ring atom is a heteroatom and the remaining atoms are carbon, the heteroatom being independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups include furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiopheneyl, benzopyridyl, benzopyrimidinyl, and benzopyrazine. The compounds include pyrrolizinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and [1,2,4]triazolo[1,5-a]pyridyl.

[0173] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-12 carbon atoms (i.e., C2-C2). 2- 12 Alkenyl), preferably containing 2-10 carbon atoms (i.e., C10). 2-10 Alkenyl), and more preferably containing 2-8 carbon atoms (i.e., C14-C24). 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6"Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0174] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-12 carbon atoms (i.e., C64-C64). 2- 12 Alkyne group), preferably containing 2-10 carbon atoms (i.e., C24-C24). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (i.e., C64-C ... 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylinyl group), 2-3 carbon atoms (i.e., C24) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0175] Unless otherwise specified, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a straight-chain or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. The term "Cx-y alkylene" (where x and y are integers) refers to a straight-chain or branched alkylene containing x to y carbon atoms, including C... 1-30 Alkylene, preferably C 1-15 Alkylene, C 1-12 Alkylene, C 1-8 Alkylene, C 1-7 Alkylene, C 1-6 Alkylene, C 1-5 Alkylene, C 1-4 Alkylene, C 1-3Alkylenes. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecanylene, octadecylene, nonadecanylene, eicosylene, icosylene, icosylene, icosylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecanylene, octadecylene, nonadecanylene, and triadecylene.

[0176] Unless otherwise specified, the "alkylene group" is optionally substituted, and the substituent is preferably one or more selected from hydroxyl, amino, mercapto, halogen, cyano, C 1-3 Alkyl, C 1-3 Substituents of alkoxy, trifluoromethyl, heterocyclic, or combinations thereof.

[0177] Unless otherwise specified, the term "ethynyl group" used alone or in combination refers to a group containing 2 to 12 carbon-carbon triple bonds, having one or more carbon-carbon triple bonds. 2-12 (ethynyl group), preferably 2 to 8 (C 2-8 (ethynyl group), preferably 2 to 6 (C 2-6 (ethynyl group), more preferably 2 to 4 (C 2-4 A straight-chain or branched divalent hydrocarbon group of a carbon atom (alkynyl group). Preferred examples of alkynyl groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

[0178] Unless otherwise specified, the term "alkenyl" used alone or in combination refers to a group having one or more carbon-carbon double bonds, comprising 2 to 12 carbon atoms (C1 to C2). 2-12 (alkenyl groups), preferably 2 to 8 (C) 2-8 (alkenyl groups), preferably 2 to 6 (C) 2-6 (alkenyl groups), more preferably 2 to 4 (C) groups. 2-4 A straight-chain or branched divalent hydrocarbon group of a carbon atom (alkenyl group). Preferred examples of alkenyl groups include, but are not limited to, vinylidene (e.g., -CH=CH-), 1-propenyl, and 1-butenyl.

[0179] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F (fluorine), Cl (chlorine), Br (bromine), and I (iodine). The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more, or all, of the hydrogen atoms are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0180] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, as defined above. Preferably, it has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Representative examples include methoxy, ethoxy, propoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0181] Unless otherwise specified, "cycloalkenyl" refers to a system composed of monocyclic, bicyclic, and spirocyclic hydrocarbon rings as daughter groups; however, the system is unsaturated, meaning it contains at least one C-C double bond but no aromatic system. Preferably, it contains 3-12 carbon atoms (i.e., C12-C22). 3-12 Cycloalkenyl), more preferably containing 3-10 carbon atoms (C 3-10 Cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 (Cycloalkenyl).

[0182] Unless otherwise specified, the terms "medicinally acceptable salt" or "medicinal salt" refer to salts that, within the limits of reasonable medical judgment, are suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio. For example, medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the relevant field.

[0183] Unless otherwise specified, the term "salt" includes salts derived from inorganic acids, as well as salts prepared from organic acids. If the compounds of the present invention are acidic, then pharmaceutically acceptable non-toxic alkalis include salts prepared from inorganic and organic bases.

[0184] Unless otherwise specified, the term "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0185] Unless otherwise specified, the term "optical isomer" refers to substances with identical molecular structures and similar physicochemical properties, but different optical rotations.

[0186] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0187] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0188] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in the body. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they can be bioavailable via oral administration, whereas the parent drug cannot. Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, is any compound of formula (I) or formula (III) that is administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0189] Unless otherwise specified, the terms "isotope-labeled analog" and "isotope derivative" refer to isotope-labeled molecules in a compound, thereby providing isotope-labeled analogs that may have improved pharmacological activity. Commonly used isotopes for isotope labeling are: hydrogen isotopes: deuterium (… 2 H) and tritium ( 3 H); Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15O, 17 O and 18 O and sulfur isotopes: 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially those with carbon. 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 The substitution of H) can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. The compounds described in this invention include their isotope derivatives, such as deuterated compounds and deuterated derivatives.

[0190] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, 6-14 membered aryl or 5-10 membered heteroarylcycloalkyl, wherein the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, 6-14 membered aryl, or 5-10 membered heteroaryl may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more of the alkoxy groups are substituted.

[0191] Unless otherwise specified, the term "multiple" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5, and more preferably 1, 2 or 3.

[0192] Unless otherwise specified, the terms "therapeutic effective amount" and "therapeutic effective dose" in this invention refer to a sufficient amount of a non-toxic drug or agent that achieves the desired effect. In embodiments of this invention, when treating a patient according to this invention, the amount of a given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics (e.g., weight) of the patient or host requiring treatment. However, depending on specific circumstances, including, for example, the specific drug used, the route of administration, the condition being treated, and the patient or host being treated, the dosage can be conventionally determined by methods known in the art. For the pharmaceutical compositions of this invention, which comprise a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier, wherein "therapeutic effective amount" refers to, based on the weight of the pharmaceutical composition, the compound of this invention constitutes 1-99% by weight, for example 20-80%, 30-70%, or 45-55%, while the pharmaceutically acceptable carrier constitutes 99-1% by weight, for example 80-20%, 70-30%, or 55-45%. Pharmaceutically acceptable carriers are those well known in the art and will not be described further here.

[0193] The beneficial effects of the present invention are one or more of the following combinations:

[0194] This invention provides a novel class of PROTAC bifunctional compounds that bind to EGFR protein and E3 ubiquitin ligase, as well as their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, and solvates. Experimental results show that the compounds of this invention:

[0195] (1) It has a good degradation effect on EGFR protein in H1975-EGFR-L858R / T790M / C797S cells;

[0196] (2) It has a good degradation effect on EGFR protein in BaF3-EGFR-L858R / T790M / C797S cells;

[0197] (3) It has a good degradation effect on EGFR protein in H1975 cells;

[0198] (4) It can significantly downregulate the expression level of pEGFR protein in H1975 cells;

[0199] (5) It has significant inhibitory activity against the proliferation of H1975-EGFR-L858R / T790M / C797S cells and / or PC9-EGFR-19del / T790M / C797S cells.

[0200] (6) It has good selectivity;

[0201] (7) It is well absorbed in mice;

[0202] (8) It can be used to treat diseases mediated by EGFR. Detailed Implementation

[0203] This invention provides a compound, or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, or deuterated compound, as shown in formula (I), (I-1), (I-2), (I-3), (I-4), or (I-5).

[0204] Where L represents the connecting chain, selected from -L1-L2-L3-L4-L5,

[0205] X; Z1, Z2, Z3, Z4; R 1 R 2 ;R 3 ;R 4 ;R 5 L1; L2, L3, L4 and L5; The definition of LBM is selected from the combination a / b / c / d / e / f / g / h / i;

[0206] a is an integer from 1 to 3, b is an integer from 1 to 7, c is an integer from 1 to 4, d is an integer from 1 to 3, e is an integer from 1 to 8, f is an integer from 1 to 9, g is an integer from 1 to 5, h is an integer from 1 to 6, i is an integer from 1 to 4. The range of the combination a / b / c / d / e / f / g / h / i is from 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 / 1 to 3 / 7 / 4 / 3 / 8 / 9 / 5 / 6 / 4.

[0207] The combination a / b / c / d / e / f / g / h / i refers to the combination of the a-th option in group A, the b-th option in group B, the c-th option in group C, the d-th option in group D, the e-th option in group E, the f-th option in group F, the g-th option in group G, the h-th option in group H, and the i-th option in group I.

[0208] Groups A, B, C, D, E, F, G, H, and I are defined as follows:

[0209] Group A: Definition of X

[0210] Group B: Definitions of Z1, Z2, Z3, and Z4

[0211] Group C: R 1 R 2 Definition

[0212] Group D: R 3 Definition

[0213] Group E: R 4 Definition

[0214] Group F: R 5 Definition

[0215] Group G: Definition of L1

[0216] Definitions of groups H: L2, L3, L4, and L5

[0217] Group I: Definition of LBM

[0218] It should be noted that the number of combinations a / b / c / d / e / f / g / h / i is 2,177,280 (=3×7×4×3×8×9×5×6×4). To save space, these combinations are represented in the above manner, just as each of the 2,177,280 combinations is specifically listed in this article.

[0219] Of the aforementioned 2,177,280 combinations, preferably without contradiction, the L-LBM is selected from: More preferably, the L-LBM is selected from: Specifically, at least one of Z2 and Z3 is R. Z CR that is not hydrogen Z More notably, both the Z2 and Z3 are CR models. Z And at least one of them is R Z CR that is not hydrogen Z Even more specifically, one of Z2 and Z3 is CH and the other is R. Z CR that is not hydrogen Z .

[0220] Of the aforementioned 2,177,280 combinations, preferably, without contradiction, at least one of Z2 and Z3 is R. Z CR that is not hydrogen Z More preferably, both Z2 and Z3 are CR Z And at least one of them is R Z CR that is not hydrogen ZMore preferably, one of Z2 and Z3 is CH and the other is R. Z CR that is not hydrogen Z .

[0221] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0222] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker AVANCE III 600MHz instrument; the LC-MS was performed using a Waters arc / QDa instrument; and the HPLC was performed using a Waters e2695_2998 instrument.

[0223] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using methods known in the art.

[0224] Preparation Examples, Examples, Test Examples, and other abbreviations used herein are:

[0225] Intermediate Preparation Example 1: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde (Intermediate 1)

[0226] Step 1: Synthesis of (1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methanol

[0227] In a 100 mL reaction flask, 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (0.50 g, 1.99 mmol), DMSO (5 mL), piperidin-4-ylmethanol (0.27 g, 2.39 mmol), and DIPEA (1.28 g, 9.95 mmol) were added sequentially. The reaction system was heated to 130 °C and reacted for 12 h. LC-MS showed that the reaction was complete. Water and DCM were added to the reaction solution, the mixture was stirred, and the liquid was separated. The organic phase was washed with water and saturated sodium chloride aqueous solution, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 45:1 (v / v)) to obtain the product (0.40 g). ESI-MS (m / z): 347.17 [M+H] + .

[0228] Step 2: Synthesis of Intermediate 1

[0229] In a 100 mL reaction flask, (1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methanol (0.38 g, 1.08 mmol) and DMF (5 mL) were added sequentially. Dysmartin oxidant (1.38 g, 3.25 mmol) was added at 0 °C. The reaction system was heated to 25 °C and reacted for 12 h. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM, washed with sodium thiosulfate, then with aqueous sodium bicarbonate solution, and finally with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 15:1 (v / v)) to give the product (0.21 g). ESI-MS (m / z): 345.13 [M+H] + .

[0230] Intermediate Preparation Example 2: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide (Intermediate 2)

[0231] Step 1: Synthesis of 3-fluoro-2-methyl-6-nitroquinoline

[0232] 2-Methyl-5-nitro-1H-indole (7.0 g, 39.73 mmol) was dissolved in xylene (70 mL), followed by the addition of 1,1-dibromo-1-fluoroethane (20.4 g, 99.10 mmol), and then potassium tert-butoxide (13.38 g, 119.24 mmol). The mixture was heated to 140 °C and reacted for 1 h. After the reaction was completed as monitored by LCMS, the reaction solution was poured into ice water, extracted with EA, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography (EA:PE = 1:50 (v / v)) to give the product (1.7 g). ESI-MS (m / z): 207.05 [M+H] + .

[0233] Step 2: Synthesis of 3-fluoro-2-methylquinoline-6-amine

[0234] 3-Fluoro-2-methyl-6-nitroquinoline (1.7 g, 8.25 mmol) was dissolved in methanol (20 mL), followed by the addition of 5% Pd / C (0.2 g). The mixture was purged three times with hydrogen and reacted at room temperature for 16 h. After the reaction was complete as monitored by LCMS, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the product (1.4 g). ESI-MS (m / z): 177.04 [M+H] + .

[0235] Step 3: Synthesis of 3-fluoro-5-iodo-2-methylquinoline-6-amine

[0236] 3-Fluoro-2-methylquinoline-6-amine (1.4 g, 7.95 mmol) was dissolved in AcOH (30 mL), and then iodine chloride (1.68 g, 10.33 mmol) was added. The reaction was carried out at 20 °C for 1 h. After the reaction was completed as monitored by LCMS, the pH was adjusted to 8 with sodium bicarbonate, and the mixture was extracted with DCM, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH = 70:1 (v / v)) to obtain the product (1.4 g). ESI-MS (m / z): 303.05 [M+H] + .

[0237] Step 4: Synthesis of (6-amino-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide

[0238] 3-Fluoro-5-iodo-2-methylquinoline-6-amine (1.3 g, 4.3 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of dimethylphosphine oxide (0.5 g, 6.46 mmol) and K3PO4 (2.7 g, 12.91 mmol), then Pd(OAc)2 (0.1 g, 0.45 mmol) and Xantphos (0.2 g, 0.346 mmol). The mixture was purged with nitrogen three times, heated to 100 °C, and reacted for 16 h. After the reaction was complete as monitored by LCMS, ice water was added, followed by extraction with EA, washing with saturated sodium chloride aqueous solution, and concentration under reduced pressure. The concentrate was then separated by silica gel column chromatography (DCM:MeOH = 70:1 (v / v)) to obtain the product (0.7 g). ESI-MS (m / z): 249.03 [M+H] + .

[0239] Step 5: Synthesis of Intermediate 2

[0240] (6-Amino-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide (0.7 g, 2.78 mmol) was dissolved in DMF (10 mL), and NaH (0.33 g, 13.88 mmol) was added. The mixture was stirred at room temperature for 0.5 h, and then 5-bromo-2,4-dichloropyrimidine (3.16 g, 13.88 mmol) was added. The reaction was carried out at room temperature for 16 h. After the reaction was completed as monitored by LCMS, ice water was added, and the mixture was extracted with EA, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH = 50:1 (v / v)) to obtain the product (0.7 g). ESI-MS (m / z): 445.17 [M+H] + .

[0241] Intermediate Preparation Example 3: Synthesis of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 3)

[0242] Step 1: Synthesis of 6-bromo-5-fluoro-1-methyl-1H-indazole-3-amine

[0243] 4-Bromo-2,5-difluorobenzonitrile (25 g, 114.68 mmol) was added to EtOH (250 mL), followed by methylhydrazine sulfate (66.12 g, 458.71 mmol) and triethylamine (104.44 g, 1.03 mol). The mixture was heated to 80 °C and reacted for 16 h. The reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated under reduced pressure, and the concentrate was poured into ice water (300 mL). Extraction was performed with EA (300 mL). The organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the product (17 g). ESI-MS (m / z): 243.98 / 245.98.

[0244] Step 2: Synthesis of 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propionic acid

[0245] 17 g (69.65 mmol) of 6-bromo-5-fluoro-1-methyl-1H-indazole-3-amine was added to 170 mL of 2N HCl, followed by 1.69 g (5.24 mmol) of TBAB and 7.53 g (104.48 mmol) of acrylic acid. The reaction mixture was heated to 100 °C and reacted for 16 h. LC-MS showed that the reaction was complete. The reaction solution was poured into 400 mL of ice water, and the pH was adjusted to 8 with sodium bicarbonate, then adjusted to approximately 5 with acetic acid. The reaction solution was extracted with EA, washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, and the organic phase was concentrated to dryness under reduced pressure to give the product (15.5 g). ESI-MS (m / z): 316.0 / 318.0 [M+H] + .

[0246] Step 3: Synthesis of Intermediate 3

[0247] 15.0 g (47.45 mmol) of 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propionic acid was added to 150 mL of AcOH, followed by 6.17 g (125.90 mmol) of NaCN. The reaction mixture was heated to 60 °C and reacted for 16 h. Then, 150 mL of 2N HCl was added, and the mixture was stirred at 60 °C for 3 h. LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction mixture was filtered. The filter cake was washed three times with water and then dried to obtain the product (6.0 g). ESI-MS (m / z): 341.00 / 343.00 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.61(s,1H),8.17(d,J=5.6Hz,1H),7.62(d,J=9.0Hz,1H),4.01(s,3H),3.93(t,J=6.8Hz,2H),2.76(t,J=6.8Hz,2H).

[0248] Intermediate Preparation Example 4: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (Intermediate 4)

[0249] Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylic acid

[0250] In a 100 mL reaction flask, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.3 g, 0.88 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.25 g, 1.32 mmol), RuPhos-Pd-G2 (0.14 g, 0.18 mmol), cesium carbonate (0.86 g, 2.65 mmol), and 1,4-dioxane (5 mL) were added sequentially. The reaction system was subjected to nitrogen protection at 120 °C for 8 h. LC-MS showed that the reaction was complete. Ethyl acetate and water were added to the reaction solution, and the mixture was stirred and separated to obtain the organic phase. The organic phase was concentrated under reduced pressure, and the concentrate was separated by column chromatography (DCM:MeOH = 40:1 (v / v)) to obtain the product (0.18 g). ESI-MS (m / z): 447.21 [M+H] + .

[0251] Step 2: Synthesis of Intermediate 4

[0252] 0.11 g (0.25 mmol) of 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in DCM (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was concentrated to dryness under reduced pressure to give crude product (0.09 g) in the form of trifluoroacetate (not shown in the figure). ESI-MS (m / z): 347.15 [M+H]+.

[0253] Intermediate Preparation Example 5: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 5)

[0254] The synthesis method was the same as in Example 3 for intermediate preparation, except that the starting material 4-bromo-2,5-difluorobenzonitrile in step 1 was replaced with 4-bromo-2-fluorobenzonitrile, yielding the product (5.8 g). ESI-MS (m / z): 322.01 / 324.00 [M+H] + .

[0255] Intermediate Preparation Example 6: Synthesis of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (Intermediate 6)

[0256] The synthesis method was the same as in Example 4 for intermediate preparation, except that the starting material 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione in step 1 was replaced with 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, yielding the product (0.08 g) in trifluoroacetate form (not shown in the figure). ESI-MS (m / z): 329.17 [M+H] + .

[0257] Intermediate Preparation Example 7: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (Intermediate 7)

[0258] Step 1: Synthesis of 5-iodoquinoxaloline-6-amine

[0259] 6-Aminoquinoxaline (1.7 g, 11.7 mmol) and DMF (20 mL) were added sequentially to a 100 mL reaction flask, followed by the slow addition of NIS (2.9 g, 12.9 mmol) at room temperature. After the addition was complete, the reaction system was allowed to continue reacting at room temperature for 2 h. LC-MS showed that the reaction was complete. Water was added, and a solid precipitated. The solid was filtered, and the filter cake was dried to obtain the product (2.4 g). ESI-MS (m / z): 271.96 [M+H] + .

[0260] Step 2: Synthesis of (6-aminoquinoxalo-5-yl)dimethylphosphine oxide

[0261] In a 100 mL reaction flask, 5-iodoquinoxaloline-6-amine (1 g, 3.7 mmol), dimethylphosphine oxide (0.45 g, 5.8 mmol), Pd(OAc)₂ (85 mg, 0.38 mmol), XantPhos (320 mg, 0.55 mmol), DIPEA (0.96 g, 7.4 mmol), and DMF (20 mL) were added sequentially. The reaction system was subjected to nitrogen protection and reacted at 120 °C for 8 h. LC-MS showed that the reaction was complete. Ethyl acetate and water were added to the reaction solution, and the mixture was stirred and separated. The resulting organic phase was concentrated to dryness under reduced pressure. The concentrate was then slurried with methyl tert-butyl ether to obtain the product (0.85 g). ESI-MS (m / z): 222.07 [M+H] + .

[0262] Step 3: Synthesis of Intermediate 7

[0263] In a 100 mL reaction flask, (6-aminoquinoxalo-5-yl)dimethylphosphine oxide (0.67 g, 3.03 mmol) and anhydrous DMF (5 mL) were added sequentially. Then, 60% NaH (0.2 g, 5.00 mmol) was added at room temperature. After stirring for 10 min, 5-bromo-2,4-dichloropyrimidine (0.8 g, 3.52 mmol) was added. The reaction system was allowed to continue reacting at room temperature for 1 h. LC-MS showed that the reaction was complete. A saturated ammonium chloride aqueous solution was added to the reaction solution, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was dried to obtain the product (1.0 g). ESI-MS (m / z): 411.97 / 413.96 [M+H] + .

[0264] Example 8: Synthesis of (2-ethyl-6-nitroquinazolin-5-yl)dimethylphosphine oxide (Intermediate 8)

[0265] Step 1: Synthesis of 2-chloro-6-fluoro-3-nitrobenzaldehyde

[0266] Under N2 protection at 0℃, 30 g (0.19 mol) of 2-chloro-6-fluorobenzaldehyde was dissolved in 10.0 mL of concentrated sulfuric acid. Then, a potassium nitrate solution in concentrated sulfuric acid (19.13 g, 0.19 mol) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the solution was slowly poured into ice water, filtered, and the filter cake was dried to obtain the product (28.00 g). LC-MS: m / z = 204.0 [M+1] + .

[0267] Step 2: Synthesis of 5-chloro-2-ethyl-6-nitroquinazoline

[0268] At room temperature, propanediidine hydrochloride (3.72 g, 34.38 mmol), DIEA (4.44 g, 34.38 mmol), and molecular sieves were dissolved in anhydrous acetonitrile (10.0 mL). After stirring for 20 minutes, 2-chloro-6-fluoro-3-nitrobenzaldehyde (5 g) was added under N2 protection. The reaction system was then heated to 80 °C and reacted for 16 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (800 mg). LC-MS: m / z = 238.1 [M+1] + .

[0269] Step 3: Synthesis of Intermediate 8

[0270] A mixture of 5-chloro-2-ethyl-6-nitroquinazoline (700 mg, 2.95 mmol), dimethylphosphine oxide (346 mg, 4.43 mmol), Pd(OAc)₂ (49.1 mg, 0.22 mmol), Xantphos (342 mg, 0.590 mmol), DIEA (763 mg, 5.90 mmol), and DMF (10.0 mL) was stirred at 120 °C for 16 h under N₂ protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1). The product (185 mg) was obtained. LC-MS: m / z = 280.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ: 10.47 (s, 1H), 8.32 (m, 2H), 3.12 (q, 2H), 2.04 (d, 6H), 1.39 (t, 3H).

[0271] Intermediate Preparation Example 9: Synthesis of (6-amino-8-fluoroquinoline-5-yl)dimethylphosphine oxide (Intermediate 9)

[0272] Step 1: Synthesis of N-(8-fluoroquinoline-6-yl)-1,1-diphenylmethyleneimine

[0273] 6-Bromo-8-fluoroquinoline (1.00 g, 4.40 mmol), diphenylmethyleneimine (800 mg, 4.40 mmol), Pd2(dba)3 (400 mg, 0.440 mmol), BINAP (550 mg, 0.880 mmol), and Cs2CO3 (2.87 g, 8.80 mmol) were dissolved in 1,4-dioxane (10.0 mL). The reaction mixture was stirred at 100 °C for 16 h under N2 protection. After cooling to room temperature and monitoring for completion, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to obtain the product (800 mg). LC-Ms: m / z = 327.0 [M+1] + .

[0274] Step 2: Synthesis of 8-fluoroquinoline-6-amine

[0275] N-(8-fluoroquinolin-6-yl)-1,1-diphenylmethyleneimine (800 mg, 2.45 mmol) was dissolved in THF (10.0 mL), and HCl solution (2.00 mL, 2N) was added. The reaction mixture was stirred at 25 °C for 1 h. After the reaction was complete, saturated NaHCO3 aqueous solution was added to adjust the pH to 8-9. The reaction mixture was extracted with EA (10.0 mL × 3), and the organic phases were combined. The organic phase was then washed with saturated sodium chloride aqueous solution (20.0 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (360 mg). LC-Ms: m / z = 163.1 [M+1] + .

[0276] Step 3: Synthesis of 8-fluoro-5-iodoquinoline-6-amine

[0277] 8-Fluoroquinoline-6-amine (750 mg, 4.63 mmol) was dissolved in AcOH (10.0 mL), and ICl (1.13 g, 6.94 mmol) was added to the reaction solution. The reaction system was stirred at 25 °C for 3 h. After the reaction was complete, saturated NaHCO3 aqueous solution was added to adjust the pH to 8-9, and the mixture was extracted with EA (10.0 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give the product (600 mg). LC-MS: m / z = 289.0 [M+1] + .

[0278] Step 4: Synthesis of Intermediate 9

[0279] 8-Fluoro-5-iodoquinoline-6-amine (580 mg, 2.01 mmol), dimethylphosphine oxide (189 mg, 2.41 mmol), Pd(OAc)₂ (33.5 mg, 0.15 mmol), Xantphos (233 mg, 0.403 mmol), and K₃PO₄ (855 mg, 4.03 mmol) were added to 1,4-dioxane (10.0 mL). The reaction mixture was stirred at 100 °C for 8 h under N₂ protection. After the reaction was monitored to be complete, the reaction system was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (173 mg). LC-MS: m / z = 239.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.54(dd,J=4.0,1.2Hz,1H),8.12(d,J=8.8Hz,1H),7.74–7 .43(m,2H),7.44(dd,J=8.8,4.0Hz,1H),6.97(dd,J=12.8,3.2Hz,1H),1.88(d,6H).

[0280] Intermediate Preparation Example 10: Synthesis of (7-amino-3-methylisoquinoline-8-yl)dimethylphosphine oxide (Intermediate 10)

[0281] Step 1: Synthesis of N-(3-chloroisoquinoline-7-yl)-1,1-diphenylmethyleneimine

[0282] At room temperature, 7-bromo-3-chloroisoquinoline (3.00 g, 12.4 mmol) and diphenylmethyleneimine (2.47 g, 13.6 mmol) were dissolved in dioxane (120 mL), and Cs₂CO₃ (8.08 g, 24.8 mmol), Pd₂(dba)₃ (1.14 g, 1.24 mmol), and BINAP (1.54 g, 2.48 mmol) were added. The reaction system was reacted at 100 °C for 14 h under nitrogen protection. After the reaction was monitored to be complete, the reaction system was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1 to 5:1) to give the product (500 mg).

[0283] Step 2: Synthesis of N-(3-methylisoquinoline-7-yl)-1,1-diphenylimine

[0284] At room temperature, N-(3-chloroisoquinoline-7-yl)-1,1-diphenylmethyleneimine (1.50 g, 4.38 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (i.e., trimethylcycloborane) (1.10 g, 8.75 mmol) were added to 1,4-dioxane (20.0 mL), followed by K₂CO₃ (1.22 g, 8.75 mmol) and Pd(dppf)Cl₂ (0.32 g, 0.438 mmol). The reaction system was subjected to nitrogen protection at 100 °C for 12 h. After monitoring the reaction to completion, the reaction system was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give the product (1.00 g).

[0285] Step 3: Synthesis of 3-methylisoquinoline-7-amine

[0286] To a THF (10.0 mL) solution of N-(3-methylisoquinoline-7-yl)-1,1-diphenylmethyleneimine (1.00 g, 3.10 mmol), HCl (1.00 mL of 12N aqueous solution) was added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was monitored to be complete, a saturated NaHCO3 aqueous solution was added to the reaction mixture to adjust the pH to 8. The mixture was then extracted with DCM (150 mL), washed with a saturated sodium chloride aqueous solution (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give the product (360 mg).

[0287] Step 4: Synthesis of 8-iodo-3-methylisoquinoline-7-amine

[0288] 3-Methylisoquinoline-7-amine (360 mg, 2.28 mmol) was dissolved in AcOH (10.0 mL), followed by the addition of ICl (443 mg, 2.73 mmol). The reaction system was stirred at room temperature for 1 h. After the reaction was monitored to be complete, a saturated NaHCO3 aqueous solution was added to the reaction system to adjust the pH to 8, and the mixture was extracted with DCM (150 mL). The organic phase was washed with a saturated sodium chloride aqueous solution (150 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give the product (500 mg).

[0289] Step 5: Synthesis of Intermediate 10

[0290] 8-Iodo-3-methylisoquinoline-7-amine (500 mg, 1.76 mmol) and dimethylphosphine oxide (207 mg, 2.64 mmol) were dissolved in 1,4-dioxane (20.0 mL), followed by the addition of K3PO4 (747 mg, 3.52 mmol), Pd(OAc)2 (29.3 mg, 0.13 mmol), and Xantphos (204 mg, 0.352 mmol). The reaction mixture was stirred at 100 °C for 14 h under nitrogen protection. After the reaction was monitored for completeness, the mixture was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1 to 5:1) to give the product (216.7 mg). LC-MS: m / z = 235.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ: 8.90 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.41 (s, 3H), 7.07 (dd, J = 9.0, 3.7Hz, 1H), 2.51 (s, 3H), 1.94 (s, 3H), 1.91 (s, 3H).

[0291] Intermediate Preparation Example 11: Synthesis of (6-aminoquinazoline-5-yl)dimethylphosphine oxide (Intermediate 11)

[0292] Step 1: Synthesis of 5-iodoquinazoline-6-amine

[0293] Quinazoline-6-amine (0.90 g, 6.21 mmol) was dissolved in DMF (10.0 mL), followed by the addition of NIS (1.82 g, 8.07 mmol). The reaction was carried out under nitrogen protection at room temperature for 2 h. After the reaction was completed, a saturated sodium bisulfite aqueous solution was added to the reaction mixture. The mixture was filtered, the solid was washed with water, and dried to give the product (1.4 g). LC-MS: m / z = 272.0 [M+1] + .

[0294] Step 2: Synthesis of Intermediate 11

[0295] A mixture of 5-iodoquinazolin-6-amine (800 mg, 2.95 mmol), dimethylphosphine oxide (346 mg, 4.43 mmol), Pd(OAc)₂ (49.1 mg, 0.22 mmol), Xantphos (342 mg, 0.590 mmol), DIEA (763 mg, 5.90 mmol), and DMF (10.0 mL) was stirred at 120 °C for 16 h under nitrogen protection. After the reaction was monitored to be complete, the reaction system was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the crude product (150 mg). The crude product was purified by preparative HPLC (Column: Gemini-C18 150x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA)) to obtain the product (57.8 mg). LC-MS: m / z = 222.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 8.96 (s, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.63 (s, 2H), 7.38 (dd, J = 9.2, 4.0 Hz, 1H), 1.93 (d, 6H).

[0296] Intermediate Preparation Example 12: Synthesis of (3-aminoquinoline-4-yl)dimethylphosphine oxide (Intermediate 12)

[0297] Step 1: Synthesis of 4-iodoquinoline-3-amine

[0298] 3-Aminoquinoline (2.00 g, 0.014 mol) and N-iodosuccinimide (3.41 g, 0.015 mol) were dissolved in 20 mL and 10 mL of DMF, respectively. The DMF solution of N-iodosuccinimide was slowly added dropwise to the DMF solution of 3-aminoquinoline at 0 °C. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (PE / EA = 5 / 1) to ensure complete reaction. A saturated aqueous solution of NaHCO3 was added to the reaction system, followed by extraction with ethyl acetate (2 x 200 mL), washing with a saturated aqueous solution of sodium chloride (200 mL), drying to anhydrous sodium sulfate, and concentrating under reduced pressure to dryness. The residue was then subjected to silica gel column chromatography (PE:EA = 1:1) to give the product (1.5 g). LC-MS: m / z = 271.0 [M+1] + .

[0299] Step 2: Synthesis of Intermediate 12

[0300] 4-Iodoquinoline-3-amine (1.5 g, 5.554 mmol), dimethylphosphine oxide (0.4 g, 5.125 mmol), and cesium carbonate (5.0 g, 15.35 mmol) were added to DMF (20 mL). Under nitrogen protection, tris(dibenzylacetone)dipalladium (0.5 g, 0.546 mmol) and bis(3,5-dimethylphenyl)phosphine oxide (0.6 g, 2.32 mmol) were added to the mixture, and the reaction was carried out overnight at 100 °C. After the reaction was complete as monitored by TLC (PE:EA = 1:1), the reaction system was cooled to room temperature. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the product (0.28 g). LC-MS: m / z = 221.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ: 8.43-8.41 (d, J=8.0Hz, 1H), 7.81-7.79 (d, J=8.0Hz, 1H), 7.68-7.66 ( d,J=8.0Hz,1H), 7.48-7.43(m,1H)), 7.41(s,2H), 7.36–7.33(m,1H), 1.94(s,3H), 1.91(s,3H).

[0301] Intermediate Preparation Example 13: Synthesis of 6-amino-5-(dimethylphosphono)quinoline-2-nitrile (Intermediate 13)

[0302] Step 1: Synthesis of 2-chloroquinoline-6-amine

[0303] At room temperature, 2-chloro-6-nitroquinoline (2.00 g, 9.59 mmol) was dissolved in ethanol (60.0 mL), followed by the addition of H₂O (12.0 mL) to reduce Fe powder (2.68 g, 47.9 mmol) and NH₄Cl (2.57 g, 47.9 mmol). The reaction mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed several times with ethanol. The filtrate was collected and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (1.30 g).

[0304] Step 2: Synthesis of 2-chloro-5-iodoquinoline-6-amine

[0305] 2-Chloroquinoline-6-amine (1.30 g, 7.28 mmol) was dissolved in glacial acetic acid (15.0 mL), and an acetic acid solution of ICl (1.42 g, 8.73 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was monitored by LCMS to ensure complete reaction. 60.0 mL of n-hexane was added to the reaction mixture for dilution, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed with n-hexane and dried under vacuum. The filter cake was dissolved in a mixed solvent of DCM:MeOH = 10:1, and washed twice with saturated Na₂CO₃ solution, twice with saturated Na₂S₂O₃ aqueous solution, and once with saturated NaCl aqueous solution. The mixture was dried over Na₂SO₄, filtered, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (1.70 g).

[0306] Step 3: Synthesis of (6-amino-2-chloroquinoline-5-yl)dimethylphosphine oxide

[0307] To a solution of 2-chloro-5-iodoquinoline-6-amine (1.00 g, 3.28 mmol) and dimethylphosphine oxide (0.27 g, 3.45 mmol) in dioxane (20.0 mL), K3PO4 (1.40 g, 6.57 mmol), Pd(OAc)2 (0.05 g, 0.22 mmol), and Xantphos (0.38 g, 0.657 mmol) were added. The reaction mixture was stirred at 100 °C for 14 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (0.6 g).

[0308] Step 4: Synthesis of Intermediate 13

[0309] Zn(CN)₂ (461 mg, 3.93 mmol) and Pd(PPh₃)₄ (227 mg, 0.196 mmol) were added sequentially to a DMF (15.0 mL) solution of (6-amino-2-chloroquinoline-5-yl)dimethylphosphine oxide (500 mg, 1.96 mmol). The reaction system was microwave-heated to 100 °C under N₂ protection and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, and the mixture was extracted twice with DCM. The organic phases were combined, washed three times with water, washed once with saturated sodium chloride aqueous solution, dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was subjected to preparative HPLC column chromatography (Column: Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: ACN-H₂O (0.1% FA)) to give the product (205 mg). LC-MS: m / z = 246.1 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ: 8.24 (d, J = 8.9 Hz, 1H), 8.00 (s, 2H), 7.85 (d, J = 9.3 Hz, 1 H),7.77(d,J=8.9Hz,1H),7.28(dd,J=9.3,4.1Hz,1H),1.92(s,3H),1.89(s,3H).

[0310] Intermediate Preparation Example 14: Synthesis of (6-amino-2-methylquinoxalin-5-yl)dimethylphosphine oxide (Intermediate 14)

[0311] The synthesis method is as described in steps 1-4 of Example 23, yielding the title compound.

[0312] Intermediate Preparation Example 15: Synthesis of (6-amino-2,3-dimethylquinoxalin-5-yl)dimethylphosphine oxide (Intermediate 15)

[0313] Step 1: Synthesis of 2,3-dimethylquinoxaloline-6-amine

[0314] At room temperature, water (6.00 mL), reduced Fe powder (687 mg, 12.3 mmol), and NH4Cl (658 mg, 12.3 mmol) were added to a 30.0 mL ethanol solution of 2,3-dimethyl-6-nitroquinoxaline (500 mg, 2.46 mmol). The mixture was heated to 90 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed several times with ethanol. The filtrate was collected and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (300 mg).

[0315] Step 2: Synthesis of 5-iodo-2,3-dimethylquinoxaloline-6-amine

[0316] At room temperature, 2,3-dimethylquinoxaloline-6-amine (300 mg, 1.73 mmol) was dissolved in glacial acetic acid (5.00 mL). An acetic acid solution of ICl (337 mg, 2.08 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until complete. A saturated NaHCO3 solution was added to the mixture to adjust the pH to 8. The mixture was then extracted with DCM (50.0 mL), washed with a saturated sodium chloride aqueous solution (50.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (350 mg).

[0317] Step 3: Synthesis of Intermediate 15

[0318] At 20 °C, K3PO4 (497 mg, 2.34 mmol), Pd(OAc)2 (19.5 mg, 0.09 mmol), and Xantphos (135 mg, 0.234 mmol) were added to a 1,4-dioxane (10.0 mL) solution of 5-iodo-2,3-dimethylquinoxaloline-6-amine (350 mg, 1.17 mmol) and dimethylphosphine oxide (137 mg, 1.76 mmol). The reaction system was heated to 100 °C and stirred for 14 hours under nitrogen protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was then subjected to preparative HPLC column chromatography (Column: Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% FA)) to obtain the product (174.5 mg). LC-MS: m / z = 250.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ: 8.37 (s, 1H), 7.77 (d, J = 9.2Hz, 1H), 2.56 (s, 3H), 2.53 (s, 3H), 1.89 (s, 3H), 1.85 (s, 3H).

[0319] Intermediate Preparation Example 16: Synthesis of (6-amino-2-cyclopropylquinoxalin-5-yl)dimethylphosphine oxide (Intermediate 16)

[0320] Step 1: Synthesis of 2-cyclopropyl-2-oxoacetaldehyde

[0321] Selenium dioxide (3.70 g, 33.3 mmol) was placed in a reaction flask, and 1,4-dioxane (20.0 mL), acetic acid (1.00 g, 16.7 mmol), and water (660 mg, 36.9 mmol) were added. The reaction system was heated to 90 °C and reacted for 2 hours. Cyclopropyl methyl ketone (2.00 g, 23.8 mmol) was then added, and the reaction was carried out at 90 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was directly used for the next reaction.

[0322] Step 2: Synthesis of 2-cyclopropyl-6-nitroquinoxaline

[0323] The filtrate of 2-cyclopropyl-2-oxoacetaldehyde obtained in step 1 was dissolved in EtOH (20.0 mL), followed by the addition of 4-nitro-o-phenylenediamine (3.12 g, 20.4 mmol) and AcOH (4.00 mL). The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction system was cooled to room temperature, and the pH was adjusted to 8-9 by adding saturated NaHCO3 aqueous solution. The resulting mixture was extracted with EA (30.0 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (40.0 mL), dried over Na2SO4, filtered, and the organic phase was concentrated to dryness under reduced pressure to obtain the product (3.00 g). LC-Ms: m / z = 216.1 [M+1] + .

[0324] Step 3: Synthesis of 2-cyclopropylquinoxaloline-6-amine

[0325] 2-Cyclopropyl-6-nitroquinoxaline (2.00 g) was added to EtOH (20.0 mL), followed by reduced iron powder (2.60 g, 46.56 mmol), NH4Cl (2.49 g, 46.5 mmol), and H2O (4.00 mL). The mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was extracted with EA (10.0 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20.0 mL), dried over Na2SO4, filtered, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (1.00 g).

[0326] Step 4: Synthesis of 2-cyclopropyl-5-iodoquinoxaline-6-amine

[0327] 2-Cyclopropylquinoxaloline-6-amine (950 mg, 5.13 mmol) was added to AcOH (10.0 mL), followed by ICl (1.25 g, 7.69 mmol). The mixture was stirred at 25 °C for 3 hours, and then the pH was adjusted to 8-9 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with EA (10.0 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20.0 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 4:1). The product was given (1.20 g; LC-MS: m / z = 312.0 [M+1]). + .

[0328] Step 5: Synthesis of Intermediate 16

[0329] 2-Cyclopropyl-5-iodoquinoxaloline-6-amine (1.10 g, 3.50 mmol), dimethylphosphine oxide (330 mg, 4.20 mmol), Pd(OAc)₂ (60.0 mg, 0.27 mmol), Xantphos (410 mg, 0.700 mmol), and K₃PO₄ (1.61 g, 7.58 mmol) were added to 1,4-dioxane (10.0 mL), and the mixture was stirred at 100 °C for 8 hours under N₂ protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the product (409 mg). LC-MS: m / z = 262.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ: 8.62 (s, 1H), 7.68 (d, J = 9.2Hz, 1H), 7.15 (dd, J = 9.2, 4.4Hz, 1H), 2.29–2.24 (m, 1H), 1.86 (d, 6H), 1.05–1.00 (m, 4H).

[0330] Intermediate Preparation Example 17: Synthesis of (6-amino-2-(trifluoromethyl)quinoline-5-yl)dimethylphosphine oxide (Intermediate 17)

[0331] Step 1: Synthesis of 1,1-diphenyl-N-(2-(trifluoromethyl)quinoline-6-yl)methylimine

[0332] A mixture of 6-bromo-2-(trifluoromethyl)quinoline (1.40 g, 5.10 mmol), diphenylmethyleneimine (1.39 g, 7.65 mmol), Pd2(dba)3 (290 mg, 0.32 mmol), BINAP (640 mg, 1.02 mmol), Cs2CO3 (3.32 g, 10.2 mmol), and 1,4-dioxane (20.0 mL) was stirred at 100 °C for 16 hours under N2 protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to give the product (1.20 g). LC-Ms: m / z = 377.1 [M+1] + .

[0333] Step 2: Synthesis of 2-(trifluoromethyl)quinoline-6-amine

[0334] HCl (3.00 mL, 2N) was added to a THF (20.0 mL) solution of 1,1-diphenyl-N-(2-(trifluoromethyl)quinolin-6-yl)methylimine (1.20 g, 3.20 mmol). The mixture was stirred at 25 °C for 1 hour. Then, saturated NaHCO3 aqueous solution was added to adjust the pH to 8-9. The resulting mixture was extracted with EA (20.0 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20.0 mL), dried over Na2SO4, filtered, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to give the product (600 mg). LC-Ms: m / z = 213.1 [M+1] + .

[0335] Step 3: Synthesis of 5-iodo-2-(trifluoromethyl)quinoline-6-amine

[0336] ICl (688 mg, 4.24 mmol) was added to a solution of 2-(trifluoromethyl)quinoline-6-amine (600 mg, 2.83 mmol) in AcOH (10.0 mL). The mixture was stirred at 25 °C for 3 hours, followed by adjustment of pH to 8-9 with saturated NaHCO3 aqueous solution. The mixture was extracted with EA (10.0 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (20.0 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to give the product (720 mg). LC-MS: m / z = 338.9 [M+1] + .

[0337] Step 4: Synthesis of Intermediate 17

[0338] A mixture of 5-iodo-2-(trifluoromethyl)quinoline-6-amine (600 mg, 1.77 mmol), dimethylphosphine oxide (166 mg, 2.13 mmol), Pd(OAc)₂ (30.0 mg, 0.16 mmol), Xantphos (205 mg, 0.355 mmol), K₃PO₄ (753 mg, 3.55 mmol), and 1,4-dioxane (10.0 mL) was stirred at 100 °C for 8 hours under N₂ protection. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1). The product (222 mg) was obtained. LC-MS: m / z = 289.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ: 8.33 (d, J = 8.8 Hz, 1H), 7.92-7.87 (m, 3H), 7.71 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 9.2, 4.0 Hz, 1H), 1.93 (d, 6H).

[0339] Intermediate Preparation Example 18: Synthesis of (6-amino-2-methylquinazoline-5-yl)dimethylphosphine oxide (Intermediate 18)

[0340] Step 1: Synthesis of 5-iodo-2-methylquinazoline-6-amine

[0341] 2-Methylquinazolin-6-amine (150 mg, 0.94 mmol) was dissolved in DMF (5 mL), and then NIS (233 mg, 1.04 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was complete as monitored by LCMS, water was added to dissolve the solid, which precipitated out. The mixture was filtered, washed, and dried to obtain the product (251 mg). ESI-MS (m / z): 286.07 [M+H] + .

[0342] Step 2: Synthesis of Intermediate 18

[0343] 5-Iodo-2-methylquinazoline-6-amine (168 mg, 0.59 mmol) was dissolved in DMF (5 mL), followed by the addition of dimethylphosphine oxide (69 mg, 0.88 mmol) and DIEA (153 mg, 1.18 mmol), then Pd(OAc)₂ (13 mg, 0.06 mmol) and Xantphos (51 mg, 0.09 mmol). The mixture was purged with nitrogen three times and reacted at 120 °C for 6 h. After LCMS analysis, the reaction was complete. Ice water was added, followed by extraction with EA, washing with saturated sodium chloride solution, and concentration under reduced pressure. The concentrate was then separated by silica gel column chromatography (DCM:MeOH = 50:1) to obtain the product (110 mg). ESI-MS (m / z): 236.11 [M+H] + .

[0344] Intermediate Preparation Example 19: Synthesis of (6-amino-2-methylquinoline-5-yl)diethylphosphine oxide (Intermediate 19)

[0345] The synthesis method was the same as in Example 18 for intermediate preparation, except that the starting material in step 1 was replaced with 2-methylquinoline-6-amine, and the starting material in step 2 was replaced with diethylphosphine oxide, yielding the product. ESI-MS (m / z): 263.25 [M+H] + .

[0346] Intermediate Preparation Example 20: Synthesis of 1-(6-(piperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 20)

[0347] Step 1: Synthesis of tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate

[0348] In a 500 mL reaction flask, 10.00 g (32.43 mmol) of 4-(5-nitropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, ethyl acetate (100 mL), tetrahydrofuran (100 mL), and Pd / C (7.00 g, 10%) were added sequentially. The reaction mixture was stirred at 30 °C under a hydrogen atmosphere (20 psi) for 16 hours. TLC (PE:EA = 1:1) showed that the reaction was complete. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to give the product (9.20 g). ESI-MS (m / z): 279.17 [M+H] + .

[0349] Step 2: Synthesis of 3-((6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridin-3-yl)amino)propionic acid

[0350] 5.00 g of 4-(5-aminopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester and 120 mL of toluene were added to a 500 mL reaction flask, followed by acrylic acid (1.42 g, 19.76 mmol). The reaction mixture was heated to 110 °C and stirred for 16 hours. TLC (DCM:MeOH = 10:1) showed the disappearance of the starting material. The reaction mixture was concentrated to dryness under reduced pressure to give the product (6.50 g). ESI-MS (m / z): 351.20 [M+H] + .

[0351] Step 3: Synthesis of 1-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0352] In a 250 mL reaction flask, 3-((6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridin-3-yl)amino)propionic acid (6.50 g, 18.55 mmol), urea (3.34 g, 55.65 mmol), and acetic acid (70 mL) were added. The reaction solution was stirred at 120 °C for 12 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product. ESI-MS (m / z): 318.15 [M+H] + .

[0353] Step 4: Synthesis of Intermediate 20

[0354] 13.00 g of crude 1-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione and HCl (70 mL, 3N) were added to a 250 mL reaction flask. The reaction solution was stirred at 50 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a solid, which was dissolved and diluted with saturated sodium bicarbonate aqueous solution, and the pH of the solution was adjusted to 7-8. This solution was then subjected to reverse reprocessing under medium pressure to obtain the product (1.32 g). ESI-MS (m / z): 276.14 [M+H] + ; 1 H NMR(400MHz,D2O)δ:7.97(s,1H),7.51(d,J=8.4Hz,1H),6.86(d,J=9.2Hz,1 H), 3.72 (t, J = 6.8Hz, 2H), 3.40 (s, 4H), 2.91 (s, 4H), 2.75 (t, J = 6.8Hz, 2H).

[0355] Intermediate Preparation Example 21: Synthesis of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 21)

[0356] The synthesis method was the same as in Intermediate Preparation Example 20, except that the starting material in step 1 was replaced with tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate to obtain the product. ESI-MS (m / z): 275.16 [M+H] + .

[0357] Intermediate Preparation Example 22: Synthesis of 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 22)

[0358] Step 1: Synthesis of tert-butyl 4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-1-carboxylic acid

[0359] In a 50 mL reaction flask, 1.86 g (7.41 mmol) of 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole, 1.90 g (6.73 mmol) of 4-(piperidin-4-ylmethyl)piperidin-1-carboxylic acid tert-butyl ester, 2.79 g (20.19 mmol) of potassium carbonate, and 15 mL of DMSO were added sequentially, and the reaction was carried out at 120 °C for 16 h. LC-MS analysis showed that the reaction was complete. The mixture was diluted with water with stirring, and a solid precipitated. The solid was filtered, and the filter cake was purified by column chromatography (DCM:MeOH = 100:1) to give the product (2.36 g). ESI-MS (m / z): 514.30 [M+H] + .

[0360] Step 2: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-4-(piperidin-4-ylmethyl)piperidine

[0361] 4-((1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (2.36 g, 4.59 mmol) and DCM (10 mL) were added to a 50 mL reaction flask. Hydrochloric acid solution (1,4-dioxane, 4 M) (1 mL) was added with stirring, and the mixture was stirred at room temperature for 0.5 h. LC-MS analysis showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and extracted with water, saturated sodium bicarbonate aqueous solution (adjusted to pH > 7), and dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate to give the product (1.79 g). ESI-MS (m / z): 414.24 [M+H] + .

[0362] Step 3: Synthesis of 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0363] In a 50 mL reaction flask, 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-4-(piperidin-4-ylmethyl)piperidine (347 mg, 0.84 mmol), 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg, 1.26 mmol), cesium carbonate (684 mg, 2.10 mmol), Pd-PEPPSI-IHeptCI (163 mg, 0.17 mmol), and 1,4-dioxane were added sequentially. The reaction was carried out at 110 °C under N2 protection for 6 h. LCMS analysis showed that the reaction was complete. The mixture was filtered, and the residue was washed with ethyl acetate. The organic phases were combined, and the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give the product (542 mg). ESI-MS (m / z): 674.31 [M+H] + .

[0364] Step 4: Synthesis of Intermediate 22

[0365] In a 25 mL reaction flask, 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (413 mg, 0.61 mmol), palladium on carbon (100 mg), and trifluoroethanol (5 mL) were added. The mixture was stirred for 2 h at room temperature under H2 atmosphere. LCMS analysis showed that the reaction was complete. The mixture was filtered, and the residue was washed with DCM. The organic phases were combined, and the reaction solution was concentrated to dryness under reduced pressure to give the product (339 mg). ESI-MS (m / z): 644.34 [M+H] + .

[0366] Intermediate Preparation Example 23: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinoxalin-5-yl)dimethylphosphine oxide (Intermediate 23)

[0367] Step 1: Synthesis of 2-methyl-6-nitroquinoxaline

[0368] 2-Chloro-6-nitroquinoxaline (1 g, 4.76 mmol), trimethylcyclotriboroxane (1.79 g, 14.29 mmol), Pd(dppf)Cl2 (696 mg, 0.95 mmol), sodium carbonate (1.01 g, 9.52 mmol), and 1,4-dioxane:water (10:1, 15 mL) were added sequentially to a 50 mL reaction flask. The reaction was carried out at 90 °C under N2 protection for 6 h. LCMS analysis showed that the reaction was complete. The reaction system was extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1) to give the product (407 mg). ESI-MS (m / z): 190.05 [M+H] + .

[0369] Step 2: Synthesis of 2-methylquinoxaloline-6-amine

[0370] 2-Methyl-6-nitroquinoxaline (1.97 g, 10.39 mmol), iron powder (2.91 g, 51.96 mmol), ammonium chloride (2.81 g, 51.96 mmol), and ethanol:water (5:1, 30 mL) were added to a 50 mL reaction flask and stirred at 80 °C for 3 h. LC-MS analysis showed the reaction was complete. The mixture was filtered, and the filtrate was collected and concentrated to dryness under reduced pressure. The residue was extracted with water and dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give the product (1.29 g). ESI-MS (m / z): 160.08 [M+H] + .

[0371] Step 3: Synthesis of 5-iodo-2-methylquinoxaloline-6-amine

[0372] In a 25 mL reaction flask, 150 mg (0.94 mmol) of 2-methylquinoxaloline-6-amine and 5 mL of DMF were added. NIS (233 mg, 1.04 mmol) was added with stirring, and the reaction was carried out at room temperature for 1 h. LC-MS analysis showed that the reaction was complete. The solid was diluted with water, filtered, and the filter cake was dried to obtain the product (218 mg). ESI-MS (m / z): 285.98 [M+H] + .

[0373] Step 4: Synthesis of (6-amino-2-methylquinoxalin-5-yl)dimethylphosphine oxide

[0374] 5-Iodo-2-methylquinoxaloline-6-amine (168 mg, 0.59 mmol), dimethylphosphine oxide (69 mg, 0.88 mmol), DIEA (153 mg, 1.18 mmol), palladium acetate (13 mg, 0.058 mmol), Xantphos (51 mg, 0.09 mmol), and DMF (5 mL) were added sequentially to a 25 mL reaction flask. The reaction was carried out at 120 °C under N2 protection for 5 h. LCMS analysis showed that the reaction was complete. The mixture was filtered, the residue was washed with DCM, the organic phase was collected, concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give the product (102 mg). ESI-MS (m / z): 236.09 [M+H] + .

[0375] Step 5: Synthesis of intermediate 23

[0376] In a 25 mL reaction flask, (6-amino-2-methylquinoxalo-5-yl)dimethylphosphine oxide (100 mg, 0.43 mmol) and DMF (5 mL) were added. NaH (26 mg, 1.08 mmol) was slowly added while stirring in an ice-water bath. The reaction was carried out at 0 °C for 20 min. Finally, 5-bromo-2,4-dichloropyrimidine (97 mg, 0.43 mmol) was added, and the reaction was carried out at room temperature for 2 h. LC-MS analysis showed the reaction was complete. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the product (95 mg). ESI-MS (m / z): 425.98 / 427.98 [M+H] + .

[0377] Intermediate Preparation Example 24: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)diethylphosphine oxide (Intermediate 24)

[0378] Step 1: Synthesis of (6-amino-3-fluoro-2-methylquinoline-5-yl)diethylphosphine oxide

[0379] 3-Fluoro-5-iodo-2-methylquinoline-6-amine (98 mg, 0.33 mmol), diethylphosphine oxide (50 mg, 0.47 mmol), Pd(OAc)₂ (8 mg, 0.036 mmol), Xantphos (29 mg, 0.05 mmol), DIEA (84 mg, 0.65 mmol), and DMF (5 mL) were added sequentially to a 25 mL reaction flask. The reaction was carried out at 120 °C under N₂ protection for 6 h. LC-MS analysis showed that the reaction was complete. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:MeOH = 50:1) to give the product (82 mg). ESI-MS (m / z): 281.11 [M+H] + .

[0380] Step 2: Synthesis of intermediate 24

[0381] In a 25 mL reaction flask, (6-amino-3-fluoro-2-methylquinoline-5-yl)diethylphosphine oxide (82 mg, 0.29 mmol) and n-butanol (5 mL) were added. While stirring, 5-bromo-2,4-dichloropyrimidine (199 mg, 0.88 mmol) and DIEA (114 mg, 0.88 mmol) were added, and the reaction was carried out at 120 °C for 2 h. LC-MS analysis showed that the reaction was complete. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 30:1) to obtain the product (22 mg). ESI-MS (m / z): 471.01 / 473.01 [M+H] + .

[0382] Intermediate Preparation Example 25: 1-(5-fluoro-1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 25)

[0383] Step 1: Synthesis of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid

[0384] Crude 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (50 mg, intermediate 4) was dissolved in DMF (5 mL), and triethylamine was added to adjust the base. Then, 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (31 mg, 0.14 mmol) and acetic acid (0.15 g, 2.53 mmol) were added, and the reaction was carried out at room temperature for 1 hour. Finally, sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added, and the reaction was carried out at room temperature for 3 hours. LCMS showed that the reaction was complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was separated by column chromatography (DCM:MeOH = 12:1 (v / v)) to give the product (45 mg). ESI-MS(m / z): 544.30[M+1]+.

[0385] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0386] The synthesis method was the same as in Intermediate Preparation Example 4, except that the starting material 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazole-6-yl)piperazin-1-carboxylic acid tert-butyl ester was replaced with 4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazole-6-yl)piperazin-1-yl)methyl)piperazin-1-carboxylic acid tert-butyl ester, yielding the product (25 mg) in trifluoroacetate form (not shown in the figure). ESI-MS (m / z): 444.24 [M+H] + .

[0387] Synthetic examples of compounds 1-111 described in Table 1 are given below. Compounds for which no specific synthetic examples are given can be synthesized by methods similar to those illustrated.

[0388] Example 1: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 1)

[0389] Step 1: Synthesis of 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0390] Crude 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (0.09 g, intermediate 4) was dissolved in DMF (5 mL), and triethylamine was added to adjust the base. Then, 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde (0.09 g, 0.26 mmol) and acetic acid (0.15 g, 2.53 mmol) were added, and the reaction was carried out at room temperature for 1 hour. Finally, sodium triacetoxyborohydride (0.16 g, 0.76 mmol) was added, and the reaction was carried out at room temperature for 3 hours. LCMS showed that the reaction was complete. The reaction solution was poured into an aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was separated by column chromatography (DCM:MeOH = 12:1 (v / v)) to give the product (0.17 g). ESI-MS (m / z): 675.23 [M+1]+.

[0391] Step 2: Synthesis of 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0392] In a 50 mL reaction flask, 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.17 g, 0.25 mmol), ethanol (5.0 mL), water (1.0 mL), reduced iron powder (0.14 g, 2.53 mmol), and ammonium chloride (0.14 g, 2.62 mmol) were added sequentially. The reaction system was reacted at 80 °C for 3 h. LC-MS showed that the reaction was complete. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, washed with saturated NaHCO3 aqueous solution, washed with saturated sodium chloride aqueous solution, and dried over anhydrous Na2SO4 to obtain the crude product (0.16 g). ESI-MS (m / z): 645.16 [M+H] + .

[0393] Step 3: Synthesis of Compound 1

[0394] In a 50 mL reaction flask, 0.16 g of crude 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, 3 mL of DMF, 0.10 g (0.23 mmol, intermediate 2) of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide, and 0.22 g (1.15 mmol) of p-toluenesulfonic acid monohydrate were added sequentially. The reaction system was heated to 100 °C and reacted for 16 h. LCMS showed the reaction was complete. Saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous Na₂SO₄. The crude product was then purified by preparative HPLC to obtain the final product (0.03 g). ESI-MS (m / z): 1051.37 / 1053.37 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 11.94(s,1H),10.53(s,1H),8.33(s,1H),8.27-8.15(m,3H),7.94(s ,1H),7.74(s,1H),7.53(m,2H),7.36(d,J=12.7Hz,1H),7.10(d,J=7.0Hz,1H),6.77(s,1H),3 .94(s,3H),3.89(m,2H),3.80(s,3H),3.77(s,3H),3.14-3.01(m,6H),2.74(m,2H),2.64-2.5 4(m,9H),2.33(m,2H),2.00(s,3H),1.98(s,3H),1.79(m,2H),1.68(s,1H),1.35-1.30(m,2H).

[0395] Example 2: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 2)

[0396] The synthesis method was the same as in step 3 of Example 1, except that intermediate 4 was replaced with intermediate 7 in the synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide, yielding the product (55 mg). ESI-MS (m / z): 1020.32 / 1022.33 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ: 12.67 (s, 1H), 10.52 (s, 1H), 8.83–8.80 (m, 3H), 8.38 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.67–7.47 (m, 2H), 7.35 (d, J = 12.8 Hz, 1H), 7.10 (d,J=7.0Hz,1H),6.83(s,1H),3.98–3.85(m,6H),3.78(m,6H),3.17–2.99(m,5H),2.7 9–2.53(m,8H),2.33(s,1H),2.00(m,7H),1.80(m,1H),1.68(s,1H),1.39–1.17(m,3H).

[0397] Example 3: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 3)

[0398] Step 1: Synthesis of 1-bromo-2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)benzene

[0399] In a 100 mL reaction flask, 4-bromo-5-fluoro-2-nitrophenol (1 g, 4.24 mmol), DMF (10 mL), cesium carbonate (4 g, 12.28 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (1.5 g, 6.46 mmol) were added sequentially. The reaction system was reacted at 50 °C for 2 h. LC-MS showed that the reaction was complete. Ethyl acetate and water were added to the reaction solution, and the mixture was stirred and separated. The resulting organic phase was washed twice with water and once with saturated sodium chloride aqueous solution, and then concentrated to dryness under reduced pressure to obtain the product (1.2 g).

[0400] Step 2: Synthesis of 4-(2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)phenyl)-1-methyl-1H-pyrazole

[0401] In a 100 mL reaction flask, 1-bromo-2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)benzene (1.2 g, 3.77 mmol), 1-methyl-1H-pyrazole-4-boric acid (0.85 g, 6.75 mmol), Pd(dppf)Cl2 (0.3 g, 0.41 mmol), potassium carbonate (1.1 g, 7.96 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially. The reaction system was subjected to N2 protection and reacted at 100 °C for 2 h. LC-MS showed that the reaction was complete. Ethyl acetate and water were added to the reaction solution, and the mixture was stirred and separated. The resulting organic phase was concentrated to dryness under reduced pressure. The concentrate was then slurried with methyl tert-butyl ether to obtain the crude product (0.63 g). ESI-MS (m / z): 320.06 [M+H] + .

[0402] Step 3: Synthesis of (1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methanol

[0403] The synthesis method followed step 1 of Example 1 for intermediate preparation, yielding the product (700 mg). ESI-MS (m / z): 415.15 [M+H] + .

[0404] Step 4: Synthesis of 1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidine-4-carboxaldehyde

[0405] The synthesis method followed step 2 of Example 1 (Intermediate Preparation) to obtain the product (650 mg). ESI-MS (m / z): 413.14 [M+H] + .

[0406] Step 5: Synthesis of 1-(5-fluoro-1-methyl-6-(4-((1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0407] The synthesis method followed step 1 of Example 1, yielding the product (200 mg). ESI-MS (m / z): 743.30 [M+H] + .

[0408] Step 6: Synthesis of 1-(6-(4-((1-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0409] The synthesis method followed step 2 of Example 1, yielding the product (180 mg). ESI-MS (m / z): 713.32 [M+H] + .

[0410] Step 7: Synthesis of Compound 3

[0411] The synthesis method followed step 3 of Example 1, yielding the product (65 mg). ESI-MS (m / z): 1088.31 / 1090.31 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 12.67(s,1H),10.54(s,1H),8.84(s,1H),8.82(s,1H),8.76(s,1H),8.52(s,1H),8.28 (s,1H),8.05(s,1H),7.84(s,1H),7.55(s,2H),7.37(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.96(s,1H),4.7 3(q,J=8.8Hz,2H),3.95(s,3H),3.90(t,J=6.6Hz,2H),3.79(s,3H),3.11(s,6H),2.75(t,J=6.6Hz,2H),2.68–2 .54(m,6H),2.34(d,J=6.8Hz,2H),2.03(s,3H),2.00(s,3H),1.81(d,J=10.8Hz,2H),1.69(s,1H),1.36(m,2H).

[0412] Example 4: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)quinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 4)

[0413] Step 1: Synthesis of quinoline-6-amine

[0414] 6-Nitroquinoline (1.00 g, 5.75 mmol) was added to ethanol (30 mL), followed by reduced iron powder (1.60 g, 28.7 mmol), ammonium chloride (3.08 g, 57.5 mmol), and water (5 mL). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The concentrate was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give the product (0.6 g). ESI-MS (m / z): 145.07 [M+H] + .

[0415] Step 2: Synthesis of 5-iodoquinoline-6-amine

[0416] Quinoline-6-amine (456 mg, 3.17 mmol) was dissolved in DMF (10 mL), and NIS (855 mg, 3.8 mmol) was added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LC-MS, the reaction mixture was poured into water (100 mL), and the aqueous phase was extracted (3 × 50 mL) with EA. The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate = 5:1 (v / v)) to give the product (640 mg). ESI-MS (m / z): 270.97 [M+H] + .

[0417] Step 3: Synthesis of (6-aminoquinoline-5-yl)dimethylphosphine oxide

[0418] 5-Iodoquinoline-6-amine (100 mg, 0.37 mmol) was dissolved in 1,4-dioxane (2 mL), and dimethylphosphine oxide (44 mg, 0.56 mmol), palladium acetate (8 mg, 0.036 mmol), Xantphos (42 mg, 0.074 mmol), and potassium phosphate (157 mg, 0.74 mmol) were added. The reaction mixture was stirred at 110 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated. The concentrate was purified by thin-layer chromatography (DCM:MeOH = 12:1 (v / v)) to give the product (70 mg). ESI-MS (m / z): 221.08 [M+H] + .

[0419] Step 4: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide

[0420] (6-aminoquinoline-5-yl)dimethylphosphine oxide (50 mg, 0.23 mmol) was dissolved in DMF (2 mL), and 5-bromo-2,4-dichloropyrimidine (77 mg, 0.34 mmol) and sodium tert-butoxide (44 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the reaction mixture was added to water (100 mL) and extracted with EA (3 × 50 mL). The organic phases were combined and concentrated. The concentrate was purified by thin-layer chromatography (DCM:MeOH = 10:1 (v / v)) to give the product (27 mg). ESI-MS (m / z): 410.97 / 412.97 [M+H] + .

[0421] Step 5: Synthesis of Compound 4

[0422] 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (54 mg, 0.084 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide (27 mg, 0.042 mmol) were dissolved in isopropanol (1 mL), and trifluoroacetic acid (0.2 mL) was added. The reaction mixture was stirred at 90 °C. After the reaction was completed as shown by LCMS, the mixture was cooled and concentrated. The concentrate was purified by thin-plate chromatography (DCM:MeOH = 8:1 (v / v)) to give the product (30 mg). ESI-MS(m / z):1019.33 / 1021.33[M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 12.37 (s, 1H), 10.53 (s, 1H), 9.50 (br, 1H), 8.78 (d, J = 3.5Hz, 1H), 8.53 (d, J = 6.0Hz, 1H), 8.43 (d, J = 8 .6Hz,1H),8.24(br,1H),8.22(s,1H),7.95(s,1H),7.82(s,1H),7.56(br,1H),7.50(dd,J=8.7,4.1Hz,1H),7.37(d,J=12.7Hz, 1H),7.12(d,J=6.1Hz,1H),6.80(s,1H),3.95(s,3H),3.89(t,J=6.6Hz,2H),3.78(s,3H),3.77(s,3H),3.14-3.04(m,12H),2.7 4(t,J=6.7Hz,2H),2.61(t,J=10.9Hz,2H),2.04(s,3H),2.02(s,3H),1.81-1.79(m,2H),1.71-1.66(m,1H),1.37-1.33(m,2H).

[0423] Example 5: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 5)

[0424] Step 1: Synthesis of 2-methylquinoline-6-amine

[0425] 2-Methyl-6-nitroquinoline (0.5 g, 2.66 mmol) was added to ethanol (10 mL), followed by reduced iron powder (0.75 g, 13.4 mmol), ammonium chloride (1.15 g, 21.2 mmol), and water (3 mL). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The concentrate was dissolved in DCM, washed with water, dried over sodium sulfate, filtered, and concentrated again to give the product (0.4 g). ESI-MS (m / z): 159.08 [M+H] + .

[0426] Step 2: Synthesis of 5-iodo-2-methylquinoline-6-amine

[0427] 2-Methylquinoline-6-amine (400 mg, 2.53 mmol) was dissolved in DMF (10 mL), and iodosuccinimide (683 mg, 3.04 mmol) was added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the reaction mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 (v / v)) to give the product (410 mg). ESI-MS (m / z): 284.98 [M+H] + .

[0428] Step 3: Synthesis of (6-amino-2-methylquinoline-5-yl)dimethylphosphine oxide

[0429] 5-Iodo-2-methylquinoline-6-amine (410 mg, 1.44 mmol) was dissolved in 1,4-dioxane (10 mL), and dimethylphosphine oxide (168 mg, 2.16 mmol), palladium acetate (31 mg, 0.14 mmol), Xantphos (162 mg, 0.28 mmol), and potassium phosphate (611 mg, 2.88 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 20:1 (v / v)) to give the product (325 mg). ESI-MS (m / z): 235.09 [M+H] + .

[0430] Step 4: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinoline-5-yl)dimethylphosphine oxide

[0431] (6-Amino-2-methylquinoline-5-yl)dimethylphosphine oxide (150 mg, 0.64 mmol) was dissolved in n-butanol (2 mL), and 5-bromo-2,4-dichloropyrimidine (190 mg, 0.83 mmol) and DIEA (165 mg, 1.28 mmol) were added. The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the reaction mixture was cooled to room temperature and filtered to obtain the product (125 mg). ESI-MS (m / z): 424.99 / 426.99 [M+H] + .

[0432] Step 5: Synthesis of Compound 5

[0433] Following the synthesis method in step 3 of Example 1, the product (25 mg) was obtained. 1H NMR(600MHz,DMSO)δ12.21(s,1H),10.54(s,1H),8.43(s,1H),8.34(s,1H),8.21(s,2H), 7.96(s,1H),7.83(s,1H),7.55(s,2H),7.42-7.33(m,2H),7.12(s,1H),6.80(s,1H),3.95 (s,3H),3.90(s,2H),3.79(s,6H),3.11(s,6H),2.75(s,2H),2.66-2.55(m,9H),2.34(s,2 H), 2.02 (s, 3H), 2.00 (s, 3H), 1.81 (d, J = 9.4Hz, 2H), 1.69 (s, 1H), 1.34 (d, J = 10.0Hz, 2H).

[0434] Example 6: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-ethylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 6)

[0435] Step 1: Synthesis of 6-nitro-2-vinylquinoline

[0436] 2-Chloro-6-nitroquinoline (624 mg, 3 mmol) was added to 1,4-dioxane (15 mL), followed by potassium trifluoroborate (804 mg, 6 mmol), Pd(dppf)Cl2 (219 mg, 0.3 mmol), potassium carbonate (828 mg, 6 mmol), and water (5 mL). The reaction mixture was stirred at 100 °C under an argon atmosphere. After the reaction was complete as shown by LC-MS, the mixture was cooled, and water (100 mL) was added. Extraction was performed with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate = 20:1 (v / v)) to give the product (350 mg). ESI-MS (m / z): 201.06 [M+H] + .

[0437] Step 2: Synthesis of 2-ethyl-6-aminoquinoline

[0438] 6-Nitro-2-vinylquinoline (350 mg, 1.75 mmol) was added to ethyl acetate (10 mL), followed by hydrated palladium on carbon (400 mg) and triethylsilane (2 mL). The reaction mixture was stirred at room temperature. LC-MS showed that the reaction was complete. The concentrate was then purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1 (v / v)) to give the product (270 mg). ESI-MS (m / z): 173.10 [M+H] + .

[0439] Step 3: Synthesis of 2-ethyl-6-amino-5-iodoquinoline

[0440] 2-Ethyl-6-aminoquinoline (270 mg, 1.57 mmol) was added to N,N-dimethylformamide (10 mL), followed by N-iodosuccinimide (424 mg, 1.88 mmol). The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LC-MS, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated, and the concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate = 4:1 (v / v)) to give the product (330 mg). ESI-MS (m / z): 299.00 [M+H] + .

[0441] Step 4: Synthesis of (2-ethyl-6-aminoquinoline-5-yl)dimethylphosphine oxide

[0442] 2-Ethyl-6-amino-5-iodoquinoline (330 mg, 1.1 mmol) was added to 1,4-dioxane (10 mL), followed by dimethylphosphine oxide (130 mg, 1.66 mmol), palladium acetate (25 mg, 0.11 mmol), Xantphos (127 mg, 0.22 mmol), and potassium phosphate (466 mg, 2.2 mmol). The reaction mixture was stirred at 110 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to give the product (260 mg). ESI-MS (m / z): 249.11 [M+H] + .

[0443] Step 5: Synthesis of (6-((2-chloro-5-bromopyrimidin-4-yl)amino)-2-ethylquinoline-5-yl)dimethylphosphine oxide

[0444] (2-Ethyl-6-aminoquinoline-5-yl)dimethylphosphine oxide (80 mg, 0.32 mmol) was added to n-butanol (2 mL), followed by 2,4-dichloro-5-bromopyrimidine (96 mg, 0.42 mmol) and diisopropylethylamine (83 mg, 0.64 mmol). The reaction mixture was stirred at 120 °C. LC-MS showed that the reaction was complete. After cooling, the mixture was filtered, the filter cake was washed with n-butanol, collected, and dried to obtain the product (80 mg). ESI-MS (m / z): 439.00 / 441.00 [M+H] + .

[0445] Step 6: Synthesis of Compound 6

[0446] 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (53 mg, 0.083 mmol) was added to isopropanol (2 mL), followed by (6-((2-chloro-5-bromopyrimidine-4-yl)amino)-2-ethylquinoline-5-yl)dimethylphosphine oxide (40 mg, 0.091 mmol) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 90 °C. After the reaction was complete, the mixture was cooled and 50 mL of sodium bicarbonate aqueous solution was added. Extraction was performed with dichloromethane (3 × 50 mL). The organic phase was dried over anhydrous sulfuric acid, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (30 mg). ESI-MS (m / z): 1047.36 / 1049.36 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 12.24 (s, 1H), 10.53 (s, 1H), 8.40 (s, 1H), 8.33 (d, J = 8.6Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.94 (s ,1H),7.83(s,1H),7.56(s,1H),7.50(s,1H),7.40-7.35(m,2H),7.11(d,J=7.0Hz,1H),6.82(s,1H),3.95(s,3H),3.89(t,J= 6.7Hz,2H),3.78(s,3H),3.77(s,3H),3.10-3.08(m,6H),2.89(q,J=7.6Hz,2H),2.74(t,J=6.7Hz,2H),2.65-2.60(m,6H),2 .35-2.33(m,2H),2.02(s,3H),2.00(s,3H),1.82-1.81(m,2H),1.70-1.66(m,1H),1.36-1.33(m,2H),1.29(t,J=7.6Hz,3H).

[0447] Example 7: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((2-cyclopropyl-5-(dimethylphosphono)quinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 7)

[0448] Step 1: Synthesis of 2-chloroquinoline-6-amine

[0449] 2-Chloro-6-nitroquinoline (1 g, 4.8 mmol) was added to ethanol (20 mL), followed by reduced iron powder (2.6 g, 48 mmol), ammonium chloride (1.3 g, 24 mmol), and water (6 mL). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The concentrate was dissolved in DCM, washed with water, dried over sodium sulfate, filtered, and concentrated again to give the product (850 mg). ESI-MS (m / z): 179.03 [M+H] + .

[0450] Step 2: Synthesis of 2-chloro-5-iodoquinoline-6-amine

[0451] 2-Chloroquinoline-6-amine (850 mg, 4.8 mmol) was added to acetic acid (15 mL), followed by iodine chloride (1.2 g, 7.39 mmol). The reaction mixture was allowed to react at room temperature for 3 h. The pH was adjusted to 8-9 by adding saturated sodium bicarbonate solution, and the resulting mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 4:1) to give the product (800 mg). ESI-MS (m / z): 304.03 [M+H] + .

[0452] Step 3: Synthesis of (6-amino-2-chloroquinoline-5-yl)dimethylphosphine oxide

[0453] 2-Chloro-5-iodoquinoline-6-amine (800 mg, 2.63 mmol) was dissolved in 1,4-dioxane (20 mL), and dimethylphosphine oxide (308 mg, 3.95 mmol), palladium acetate (58.4 mg, 0.26 mmol), Xantphos (301 mg, 0.52 mmol), and potassium phosphate (1.12 g, 5.26 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the product (480 mg). ESI-MS (m / z): 255.04 [M+H] + .

[0454] Step 4: Synthesis of (6-amino-2-cyclopropylquinoline-5-yl)dimethylphosphine oxide

[0455] (6-amino-2-chloroquinoline-5-yl)dimethylphosphine oxide (100 mg, 0.39 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Cyclopropylboronic acid (67 mg, 0.78 mmol), palladium acetate (9 mg, 0.04 mmol), triphenylphosphine (21 mg, 0.08 mmol), and cesium carbonate (257 mg, 0.8 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. After the reaction was complete as shown by LC-MS, the mixture was cooled, filtered, and the filtrate was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the product (20 mg). ESI-MS (m / z): 261.11 [M+H] + .

[0456] Step 5: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-cyclopropylquinoline-5-yl)dimethylphosphine oxide

[0457] (6-amino-2-cyclopropylquinoline-5-yl)dimethylphosphine oxide (20 mg, 0.08 mmol) was dissolved in n-butanol (2 mL), and 5-bromo-2,4-dichloropyrimidine (35 mg, 0.154 mmol) and DIEA (31 mg, 0.24 mmol) were added. The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LC-MS, the reaction mixture was concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 30:1 (v / v)) to give the product (14 mg). ESI-MS (m / z): 451.03 / 453.03 [M+H] + .

[0458] Step 6: Synthesis of Compound 7

[0459] Following the synthesis method in step 3 of Example 1, the product (7 mg) was obtained. ESI-MS (m / z): 1059.36 / 1061.36 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 12.20 (s, 1H), 10.53 (s, 1H), 8.37-8.31 (m, 2H), 8.29-8.23 (m, 2H), 8.18 (s, 1H), 7.93 (s, 1H),7.83(s,1H),7.44(s,1H),7.40(d,J=8.9Hz,1H),7.36(d,J=12.9Hz,1H),7.10(d,J=6.9Hz,1H),6.82(s,1H),3 .94(s,3H),3.91-3.87(m,2H),3.78-.375(m,6H),3.13-3.07(m,6H),2.76-2.72(m,2H),2.67–2.58(m,6H),2.37-2 .32(m,2H),2.00(s,3H),1.98(s,3H),1.85-1.81(m,2H),1.73-1.67(m,1H),1.38-1.32(m,3H),1.05-1.01(m,4H).

[0460] Example 8: 6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(dimethylphosphono)quinoline-2-onitrile (Compound 8)

[0461] The synthesis method was as described in Example 4, yielding a product (21 mg). ESI-MS (m / z): 1044.31 / 1046.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 12.57(s,1H),10.53(s,1H),8.63(s,1H),8.61(s,1H),8.36(s,1H),8.28(s,1H),8.00(s,1H), 7.94(d,J=8.9Hz,1H),7.73(s,1H),7.55(s,2H),7.37(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.82(s,1H),3.95(s,3H ),3.90(t,J=6.7Hz,2H),3.80(m,6H),3.11(s,3H),3.07(d,J=10.8Hz,2H),2.75(t,J=6.7Hz,2H),2.60-2.63(m,5H),2. 34(d,J=5.8Hz,2H),2.07(s,3H),2.04(s,3H),1.81(d,J=11.0Hz,2H),1.70(s,1H),1.35(d,J=10.7Hz,3H),1.24(s,2H).

[0462] Example 9: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-(trifluoromethyl)quinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 9)

[0463] Step 1: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-(trifluoromethyl)quinoline-5-yl)dimethylphosphine oxide

[0464] The synthesis method followed step 3 of Example 7 (Intermediate Preparation), yielding the product (85 mg). ESI-MS (m / z): 478.96 / 480.96 [M+H] + .

[0465] Step 2: Synthesis of Compound 9

[0466] The synthesis method was performed according to step 3 of Example 1, yielding the product (15 mg). ESI-MS (m / z): 1087.32 / 1089.31 [M+H]+. 1 H NMR (600MHz, DMSO-d6) δ: 12.47(s,1H),10.53(s,1H),8.76–8.66(m,1H),8.57(s,1H),8.37(s,1H),8.26(s,1 H),7.99(s,1H),7.90-7.82(m,1H),7.78–7.61(m,2H),7.51(s,1H),7.37(d,J=12.8Hz,1H),7.11(d,J=7.1Hz, 1H),6.84(s,1H),3.95(s,3H),3.90(t,J=6.7Hz,3H),3.84–3.74(m,6H),3.18–3.00(m,5H),2.80-2.70(m,2H) ,2.69–2.52(m,6H),2.38–2.25(m,2H),2.07-2.00(m,6H),1.85–1.76(m,2H),1.68(s,1H),1.35-1.28(m,2H).

[0467] Example 10: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((2-(difluoromethyl)-5-(dimethylphosphono)quinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 10)

[0468] Step 1: Synthesis of 6-nitroquinoline-2-carboxaldehyde

[0469] 2-Methyl-6-nitroquinoline (0.5 g, 2.66 mmol) was added to DMSO (10 mL), along with iodine (0.54 g, 2.13 mmol) and trifluoroacetic acid (0.46 g, 3.99 mmol). The reaction mixture was stirred at 130 °C under air. After the reaction was complete as shown by LCMS, the reaction system was cooled to room temperature, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3 (v / v)) to give the product (345 mg). ESI-MS (m / z): 203.04 [M+H] + .

[0470] Step 2: Synthesis of 2-(difluoromethyl)-6-nitroquinoline

[0471] 6-Nitroquinoline-2-carboxaldehyde (345 mg, 1.71 mmol) was added to DCM (10 mL), and diethylaminosulfur trifluoride (551 mg, 3.42 mmol) was slowly added at 0 °C. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (10 mL) was added, and the aqueous phase was extracted with DCM (2 × 10 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:2 (v / v)) to give the product (260 mg). ESI-MS (m / z): 225.04 [M+H] + .

[0472] Step 3: Synthesis of 2-(difluoromethyl)quinoline-6-amine

[0473] 2-(difluoromethyl)-6-nitroquinoline (260 mg, 1.16 mmol) was added to ethanol (10 mL), followed by reduced iron powder (325 mg, 5.8 mmol), ammonium chloride (501 mg, 9.37 mmol), and water (3 mL). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The concentrate was dissolved in DCM, washed with water, dried over sodium sulfate, filtered, and concentrated again to give the product (215 mg). ESI-MS (m / z): 195.07 [M+H] + .

[0474] Step 4: Synthesis of 2-(difluoromethyl)-5-iodoquinoline-6-amine

[0475] 2-(difluoromethyl)quinoline-6-amine (215 mg, 1.11 mmol) was dissolved in DMF (10 mL), and iodosuccinimide (300 mg, 1.33 mmol) was added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the reaction mixture was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v / v)) to give the product (290 mg). ESI-MS (m / z): 320.96 [M+H] + .

[0476] Step 5: Synthesis of (6-amino-2-(difluoromethyl)quinoline-5-yl)dimethylphosphine oxide

[0477] 2-(difluoromethyl)-5-iodoquinoline-6-amine (290 mg, 0.91 mmol) was dissolved in 1,4-dioxane (10 mL), and dimethylphosphine oxide (106 mg, 1.37 mmol), palladium acetate (20.2 mg, 0.09 mmol), Xantphos (104 mg, 0.18 mmol), and potassium phosphate (382 mg, 1.8 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated. The concentrate was slurried with ethyl acetate and methyl tert-butyl ether (1:1 (v / v)) to give the product (250 mg). ESI-MS (m / z): 271.07 [M+H] + .

[0478] Step 6: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-(difluoromethyl)quinoline-5-yl)dimethylphosphine oxide

[0479] (6-Amino-2-(difluoromethyl)quinoline-5-yl)dimethylphosphine oxide (150 mg) was dissolved in n-butanol (2 mL), and 5-bromo-2,4-dichloropyrimidine (165 mg, 0.73 mmol) and DIEA (145 mg, 1.12 mmol) were added. The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the reaction mixture was cooled to room temperature and concentrated. The concentrate was purified by thin-layer chromatography (dichloromethane:methanol = 50:1 (v / v)) to give the product (40 mg). ESI-MS (m / z): 460.97 / 462.97 [M+H] +

[0480] Step 7: Synthesis of Compound 10

[0481] Following the synthesis method in step 3 of Example 1, the product (25 mg) was obtained. ESI-MS (m / z): 1069.32 / 1071.32 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 12.43(s,1H),10.53(s,1H),8.63(s,1H),8.58(s,1H),8.30(s,1H),8.25(s,1H),7. 97(s,1H),7.78(s,1H),7.72(d,J=7.7Hz,1H),7.62(s,1H),7.55(s,1H),7.36(d,J=12.4Hz,1H),7.18-7.03( m,2H),6.81(s,1H),3.95(s,3H),3.90(s,2H),3.79(s,3H),3.77(s,3H),3.11-3.06(m,6H),2.74(s,2H),2.6 7-2.57(m,6H),2.36(s,2H),2.06(s,3H),2.04(s,3H),1.80(d,J=9.2Hz,2H),1.68(s,1H),1.38-1.28(m,2H).

[0482] Example 11: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)quinazolin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 16)

[0483] Step 1: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinazolin-5-yl)dimethylphosphine oxide

[0484] The synthesis method followed step 3 of Example 7 (Intermediate Preparation) to obtain the product (40 mg). ESI-MS (m / z): 411.97 / 413.97 [M+H] + .

[0485] Step 2: Synthesis of Compound 16

[0486] The synthesis method was performed according to step 3 of Example 1, yielding the product (20 mg). ESI-MS (m / z): 1020.32 / 1022.32 [M+H]+. 1H NMR (600MHz, DMSO-d6) δ: 12.20(s,1H),10.53(s,1H),9.67(s,1H),9.22(s,1H),8.67(s,1H),8.33–8.22( m,2H),7.96(s,1H),7.72(s,1H),7.61–7.44(m,2H),7.36(d,J=12.7Hz,1H),7.11(d,J=6.5Hz,1H),6.80( s,1H),3.95(s,3H),3.90(t,J=6.2Hz,2H),3.83-3.74(m,6H),3.12–3.04(m,6H),2.76-2.71(m,2H),2.64 –2.56(m,6H),2.34(s,2H),2.11(s,3H),2.09(s,3H),1.84–1.76(m,2H),1.68(s,1H),1.39-1.30(m,2H).

[0487] Example 12: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 17)

[0488] The synthesis method was as described in Example 4, yielding a product (18 mg). ESI-MS (m / z): 1034.34 / 1036.34 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ: 12.00(s,1H),10.52(s,1H),9.60(s,1H),8.55(s,1H),8.23(s,2H),7.94(s,1H),7.72 (s,1H),7.54-7.45(m,2H),7.36(d,J=12.7Hz,1H),7.10(d,J=6.9Hz,1H),6.78(s,1H),3.94(s,3H),3.89(t,J= 6.5Hz,2H),3.78(d,J=3.7Hz,6H),3.10(s,3H),3.05(d,J=10.2Hz,2H),2.73-2.75(m,4H),2.59-2.61(m,6H),2 .33(d,J=5.4Hz,2H),2.08(s,3H),2.06(s,3H),1.97-2.02(m,2H),1.80(m,2H),1.66(s,1H),1.29-1.38(m,2H).

[0489] Example 13: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 18)

[0490] The synthesis method was as described in Example 4, yielding the product (9 mg). ESI-MS (m / z): 1048.31 / 1050.33 [M+H] + .

[0491] Example 14: Synthesis of 1-(6-(4-((1-(4-((4-((5-(dimethylphosphono)quinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 38)

[0492] Step 1: Synthesis of (6-((2-chloropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide

[0493] (6-aminoquinoline-5-yl)dimethylphosphine oxide (206 mg, 0.94 mmol) was added to 1,4-dioxane (10 mL), followed by 2-chloro-4-bromopyrimidine (272 mg, 1.4 mmol), Pd2(dba)3 (86 mg, 0.09 mmol), BINAP (112 mg, 0.18 mmol), and cesium carbonate (919 mg, 2.82 mmol). The reaction mixture was stirred at 120 °C under an argon atmosphere. After the reaction was complete as shown by LC-MS, the mixture was cooled and added to water (100 mL). Extraction was performed using EA (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel thin-plate chromatography (dichloromethane:methanol = 12:1 (v / v)) to give the product (80 mg). ESI-MS (m / z): 333.06 / 335.06 [M+H] + .

[0494] Step 2: Synthesis of Compound 38

[0495] (6-((2-chloropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide (40 mg, 0.12 mmol) and 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (64 mg, 0.1 mmol) were added to isopropanol (1 mL), followed by trifluoroacetic acid (0.2 mL). The reaction mixture was stirred at 90 °C. After the reaction was complete, the mixture was cooled and added to an aqueous sodium bicarbonate solution (100 mL). Extraction was performed with dichloromethane (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel thin-plate chromatography (DCM:MeOH = 10:1 (v / v)) to give the product (40 mg). ESI-MS (m / z): 941.42 [M+H] +,1H NMR (600MHz, DMSO-d6) δ: 12.27 (s, 1H), 10.53 (s, 1H), 8.84 (d, J = 6.0Hz, 1H), 8.78 (d, J = 3.5Hz, 1H), 8.50 (d, J = 8.6Hz, 1H), 8.06 (d, J = 5.6 Hz,1H),8.02(s,1H),7.95(s,1H),7.86(s,1H),7.84(s,1H),7.65(br,1H),7.51(dd,J=8.7,4.1Hz,1H),7.36(d,J=12.8Hz,1H),7.11(d,J =7.0Hz,1H),6.83(s,1H),6.09(d,J=5.6Hz,1H),3.94(s,3H),3.89(t,J=6.7Hz,2H),3.83(s,3H),3.80(s,3H),3.11-3.06(m,6H),2.74(t ,J=6.7Hz,2H),2.64-2.59(m,6H),2.33-2.32(m,2H),2.05(s,3H),2.03(s,3H),1.81-1.80(m,2H),1.70-1.66(m,1H),1.38-1.31(m,2H).

[0496] Example 15: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((4-(dimethylphosphono)quinoline-3-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 39)

[0497] Step 1: Synthesis of (3-((2-chloro-5-bromopyrimidin-4-yl)amino)quinoline-4-yl)dimethylphosphine oxide

[0498] (3-aminoquinoline-4-yl)dimethylphosphine oxide (52 mg, 0.24 mmol) was added to N,N-dimethylformamide (5 mL), followed by 2,4-dichloro-5-bromopyrimidine (107 mg, 0.47 mmol) and sodium tert-butoxide (45 mg, 0.47 mmol). The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 30:1 (v / v)) to give the product (31 mg). ESI-MS (m / z): 410.97 / 412.97 [M+H] + .

[0499] Step 2: Synthesis of Compound 39

[0500] 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (49 mg, 0.076 mmol) was added to isopropanol (2 mL), followed by (3-((2-chloro-5-bromopyrimidine-4-yl)amino)quinoline-4-yl)dimethylphosphine oxide (31 mg, 0.076 mmol) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 90 °C. After the reaction was complete as shown by LCMS, the mixture was cooled and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (9 mg). ESI-MS(m / z):1019.33 / 1021.33[M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 11.97 (s, 1H), 10.53 (s, 1H), 9.55 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 8.06 (d, J = 8.2Hz, 1H), 7.90 ( d,J=7.7Hz,1H),7.80(s,1H),7.75(s,1H),7.68-7.65(m,1H),7.63-7.60(m,1H),7.53(s,1H),7.36(d,J=12.3Hz,1H),7.11 (s,1H),6.78(s,1H),3.95(s,3H),3.89(t,J=6.7Hz,2H),3.82(s,3H),3.71(s,3H),3.11-3.04(m,6H),2.74(t,J=6.6Hz,2H ),2.59-2.56(m,6H),2.32-2.31(m,2H),2.09(s,3H),2.07(s,3H)2.02-1.96(m,2H),1.80-1.78(m,2H),1.68-1.65(m,1H).

[0501] Example 16: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(diethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 40)

[0502] Step 1: Synthesis of (6-aminoquinoxalo-5-yl)diethylphosphine oxide

[0503] The synthesis method followed step 2 of Example 7 (Intermediate Preparation), yielding the product (0.47 g). ESI-MS (m / z): 250.10 [M+H] + .

[0504] Step 2: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)diethylphosphine oxide

[0505] The synthesis method followed step 3 of Example 7 (Intermediate Preparation), yielding the product (140 mg). ESI-MS (m / z): 440.00 / 442.00 [M+H] + .

[0506] Step 3: Synthesis of Compound 40

[0507] The synthesis method followed step 3 of Example 1, yielding the product (50 mg). ESI-MS (m / z): 1048.35 / 1050.35 [M+H] + . 1 H NMR(600MHz, DMSO-d6)δ: 12.76(s,1H),10.53(s,1H),8.90–8.76(m,3H),8.38(s,1H),8.28(s,1H),8.00(s, 1H),7.72(s,1H),7.66–7.47(m,2H),7.36(d,J=12.8Hz,1H),7.10(d,J=7.0Hz,1H),6.84(s,1H),3.94(s,3H ),3.89(t,J=6.6Hz,2H),3.80(s,3H),3.76(s,3H),3.11(s,6H),2.74(t,J=6.6Hz,2H),2.65-2.59(m,6H),2 .43–2.30(m,4H),2.29–2.19(m,2H),1.87–1.76(m,2H),1.68(s,1H),1.37-1.30(m,2H),1.00-0.95(m,6H).

[0508] Example 17: Synthesis of 1-(6-(4-((1-(4-((4-((5-(dimethylphosphono)quinoline-6-yl)amino)-5-fluoropyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 41)

[0509] Step 1: Synthesis of (6-((2-chloro-5-fluoropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide

[0510] In a 25 mL reaction flask, (6-aminoquinoline-5-yl)dimethylphosphine oxide (70 mg, 0.32 mmol), 2,4-dichloro-5-fluoropyrimidine (69 mg, 0.41 mmol), and n-butanol (5 mL) were added sequentially. DIEA (83 mg, 0.64 mmol) was added dropwise with stirring, and the reaction was carried out at 120 °C for 5 h. LC-MS showed that the reaction was complete. Ethyl acetate and water were added to the reaction solution, the organic phase was separated, the solvent was removed by rotary evaporation, and the product (24 mg) was purified by column chromatography (DCM:MeOH = 30:1). ESI-MS (m / z): 351.45 [M+H] + .

[0511] Step 2: Synthesis of compound 41.

[0512] In a 25 mL reaction flask, (6-((2-chloro-5-fluoropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide (24 mg, 0.07 mmol), 1-(6-(4-(1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-112-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (39 mg, 0.06 mmol), and n-butanol (5 mL) were added sequentially. TFA (68 mg, 0.60 mmol) was added dropwise with stirring, and the reaction was carried out at 120 °C for 16 h. LC-MS showed that the reaction was complete. Ethyl acetate and water were added to the reaction solution, the organic phase was separated, concentrated to dryness under reduced pressure, and purified by thin-layer chromatography (DCM:MeOH = 15:1) to obtain the product (14 mg). ESI-MS (m / z): 959.50 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 12.97 (s, 1H), 10.53 (s, 1H), 9.02 (s, 1H), 8.80 (d, J = 3.5Hz, 1H), 8.41 (d, J = 8.8Hz, 1H), 8.13 (d, J = 3.2Hz, 1 H),8.07(s,1H),8.03(s,1H),7.86(s,1H),7.70(s,1H),7.61(s,1H),7.53(dd,J=8.7,4.1Hz,1H),7.37(d,J=12.8Hz,1H),7.12(d,J= 7.0Hz,1H),6.84(s,1H),3.95(s,3H),3.90(t,J=6.7Hz,2H),3.81(m,6H),3.12(s,6H),2.75(t,J=6.6Hz,2H),2.65(d,J=11.4Hz,2H) ,2.61(d,J=9.4Hz,3H),2.34(d,J=6.7Hz,2H),2.08(s,3H),2.06(s,3H),1.82(d,J=11.5Hz,2H),1.70(s,1H),1.35(d,J=9.7Hz,2H).

[0513] Example 18: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((8-(dimethylphosphono)-3-methylisoquinoline-7-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 42)

[0514] Step 1: Synthesis of (7-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-methylisoquinoline-8-yl)dimethylphosphine oxide

[0515] The synthesis method followed step 3 of Example 7 (Intermediate Preparation) to obtain the product (100 mg). ESI-MS (m / z): 424.99 / 426.98 [M+H] + .

[0516] Step 2: Synthesis of Compound 42

[0517] The synthesis method was performed according to step 3 of Example 1, yielding the product (38 mg). ESI-MS (m / z): 1033.34 / 1035.34 [M+H]+. 1 H NMR (600MHz, DMSO-d6) δ: 12.24(s,1H),10.54(s,1H),9.28(s,1H),8.38(s,1H),8.22(s,1H),8.16(s,1H ),7.88(s,1H),7.82(s,1H),7.60(s,1H),7.47–7.32(m,3H),7.11(d,J=7.1Hz,1H),6.78(s,1H),3.95(s, 3H),3.90(m,2H),3.79(s,3H),3.72(s,3H),3.11(s,3H),3.04(m,3H),2.75(t,J=6.7Hz,2H),2.59-2.54( m,9H),2.33(d,J=6.1Hz,2H),2.12-2.07(m,6H),1.80(d,J=11.2Hz,2H),1.68(s,1H),1.35-1.28(m,2H).

[0518] Example 19: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((2-cyclopropyl-5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 43)

[0519] Step 1: Synthesis of 2-cyclopropyl-3-fluoro-6-nitroquinoline

[0520] 2-Chloro-3-fluoro-6-nitroquinoline (1 g, 4.4 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). Cyclopropylboronic acid (1.6 g, 18.6 mmol), palladium acetate (108 mg, 0.48 mmol), triphenylphosphine (250 mg, 0.96 mmol), and cesium carbonate (4.7 g, 14.4 mmol) were added. The reaction mixture was stirred under N2 protection at 100 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled, filtered, and the filtrate was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (EA:PE = 1:40 (v / v)) to give the product (172 mg). ESI-MS (m / z): 233.16 [M+H] + .

[0521] Step 2: Synthesis of 2-cyclopropyl-3-fluoroquinoline-6-amine

[0522] 2-Cyclopropyl-3-fluoro-6-nitroquinoline (170 mg, 0.73 mmol) was added to ethanol (10 mL), followed by reduced iron powder (205 mg, 3.65 mmol), ammonium chloride (376 mg, 7.03 mmol), and water (3 mL). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The concentrate was dissolved in DCM, washed with water, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to dryness to give the product (155 mg). ESI-MS (m / z): 203.09 [M+H] + .

[0523] Step 3: Synthesis of 2-cyclopropyl-3-fluoro-5-iodoquinoline-6-amine

[0524] 2-Cyclopropyl-3-fluoroquinoline-6-amine (155 mg, 0.77 mmol) was dissolved in DMF (5 mL), and iodosuccinimide (207 mg, 0.92 mmol) was added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the reaction mixture was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (EA:Pe = 1:3 (v / v)) to give the product (50 mg). ESI-MS (m / z): 328.99 [M+H] + .

[0525] Step 4: Synthesis of (6-amino-2-cyclopropyl-3-fluoroquinoline-5-yl)dimethylphosphine oxide

[0526] 2-Cyclopropyl-3-fluoro-5-iodoquinoline-6-amine (50 mg, 0.15 mmol) was dissolved in 1,4-dioxane (10 mL), and dimethylphosphine oxide (18 mg, 0.23 mmol), palladium acetate (4 mg, 0.018 mmol), Xantphos (17.6 mg, 0.03 mmol), and potassium phosphate (65 mg, 0.306 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 25:1 (v / v)) to give the product (40 mg). ESI-MS (m / z): 279.10 [M+H] + .

[0527] Step 5: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3-fluoroquinoline-5-yl)dimethylphosphine oxide

[0528] (6-Amino-2-cyclopropyl-3-fluoroquinoline-5-yl)dimethylphosphine oxide (40 mg, 0.14 mmol) was dissolved in n-butanol (2 mL), and 5-bromo-2,4-dichloropyrimidine (42 mg, 0.18 mmol) and DIEA (36.2 mg, 0.28 mmol) were added. The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LC-MS, the reaction mixture was concentrated, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 40:1 (v / v)) to give the product (20 mg). ESI-MS (m / z): 468.99 / 470.99 [M+H] + .

[0529] Step 6: Synthesis of Compound 43

[0530] Following the synthesis method in step 3 of Example 1, the product (6 mg) was obtained. 1H NMR (600MHz, DMSO-d6) δ: 12.03(s,1H),10.53(s,1H),8.33-8.22(m,2H),8.20(s,1H),8.15-8.09(m,1H),7.93( s,1H),7.77(s,1H),7.48-7.40(m,2H),7.36(d,J=12.5Hz,1H),7.11(d,J=6.1Hz,1H),6.81(s,1H),3.95(s,3H), 3.91–3.86(m,2H),3.77(s,6H),3.17–3.03(m,6H),2.77-2.70(m,2H),2.69-2.55(m,6H),2.37-2.31(m,2H),2.0 0(s,3H),1.98(s,3H),1.86-1.79(m,2H),1.73-1.67(m,1H),1.49-1.43(m,1H),1.38-1.32(m,2H),1.23(s,4H).

[0531] Example 20: Synthesis of 1-(6-(4-((1-(4-((5-chloro-4-((5-(dimethylphosphono)quinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 44)

[0532] Step 1: Synthesis of (6-((2,5-dichloropyrimidin-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide

[0533] (6-Aminoquinoline-5-yl)dimethylphosphine oxide (60 mg, 0.27 mmol) was added to isopropanol (1 mL), followed by 2,4,5-trichloropyrimidine (47 mg, 0.26 mmol) and diisopropylethylamine (209 mg, 1.62 mmol). The reaction mixture was stirred at 90 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled, and water (50 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol: 12:1 (v / v)) to give the product (32 mg). ESI-MS (m / z): 367.02 / 369.02 [M+H] + .

[0534] Step 2: Synthesis of Compound 44

[0535] 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (56 mg, 0.087 mmol) was added to isopropanol (1 mL), followed by (6-((2,5-dichloropyrimidine-4-yl)amino)quinoline-5-yl)dimethylphosphine oxide (32 mg, 0.087 mmol) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 90 °C. After the reaction was complete as indicated by LCMS, the mixture was cooled, and an aqueous solution of sodium bicarbonate (100 mL) was added to the mixture. The mixture was extracted with ethyl acetate (3 × 50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 8:1 (v / v)) to give the product (18 mg). ESI-MS (m / z): 975.38 / 977.38 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 12.62 (s, 1H), 10.53 (s, 1H), 8.78 (d, J = 3.7Hz, 1H), 8.70 (s, 1H), 8.42 (d, J = 8.6Hz, 1H), 8.27 (s, 1H), 8 .15(s,1H),7.98(s,1H),7.84(s,1H),7.62-7.57(m,2H),7.50(dd,J=8.7,4.1Hz,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=6.9Hz ,1H),6.82(s,1H),3.95(s,3H),3.89(t,J=6.7Hz,2H),3.79(s,3H),3.78(s,3H),3.10-3.08(m,6H),2.74(t,J=6.7Hz,2H),2.6 8-2.60(m,6H),2.33(d,J=6.5Hz,2H),2.05(s,3H),2.03(s,3H),1.80(d,J=11.3Hz,2H),1.73-1.67(m,1H),1.38-1.32(m,2H).

[0536] Example 21: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 45)

[0537] The synthesis method was as described in Example 4, yielding a product (19 mg). ESI-MS (m / z): 1034.34 / 1036.34 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ: 12.55(s,1H),10.53(s,1H),8.62(s,2H),8.36(s,1H),8.27(s,1H),8.00(s,1H),7.80 (s,1H),7.59(s,1H),7.49(s,1H),7.37(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.83(s,1H),3.95(s,3H),3.9 0(t,J=6.7Hz,2H),3.81(s,3H),3.79(s,3H),3.11-3.09(m,6H),2.75(t,J=6.7Hz,2H),2.66(s,3H),2.64-2.61 (m,6H),2.35-2.33(m,2H),2.02(s,3H),2.00(s,3H),1.83-1.81(m,2H),1.72-1.68(m,1H),1.38-1.33(m,2H).

[0538] Example 22: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((2-cyclopropyl-5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 46)

[0539] The synthesis method was as described in Example 4, yielding a product (27 mg). ESI-MS (m / z): 1060.35 / 1062.35 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ: 12.49(s,1H),10.54(s,1H),8.83(s,1H),8.60(s,1H),8.40(s,1H),8.24(s,1H),7.96(s,1H),7.80( s,1H),7.50(s,1H),7.41(d,J=12.7Hz,1H),7.37(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.86(s,1H),3.95(s,3H),3.90(t,J =6.6Hz,2H),3.80(s,3H),3.76(s,3H),3.13(s,5H),2.75(t,J=6.7Hz,2H),2.64-2.68(m,2H),2.62(s,3H),2.35-2.39(m,3H) ,2.00(d,J=14.4Hz,6H),1.83(d,J=11.1Hz,2H),1.71(s,1H),1.36-1.40(m,3H),1.24(s,2H),1.13-1.14(m,2H),1.08(s,2H).

[0540] Example 23: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-8-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 47)

[0541] Step 1: Synthesis of (6-((2-chloro-5-bromopyrimidin-4-yl)amino)-8-fluoroquinoline-5-yl)dimethylphosphine oxide

[0542] (6-amino-8-fluoroquinoline-5-yl)dimethylphosphine oxide (46 mg, 0.19 mmol) was added to n-butanol (1 mL), followed by 2,4-dichloro-5-bromopyrimidine (60 mg, 0.26 mmol) and diisopropylethylamine (52 mg, 0.4 mmol). The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and water (50 mL) was added. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 30:1 (v / v)) to give the product (27 mg). ESI-MS (m / z): 428.96 / 430.96 [M+H] + .

[0543] Step 2: Synthesis of Compound 47

[0544] 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (45 mg, 0.069 mmol) was added to isopropanol (1 mL), followed by (6-((2-chloro-5-bromopyrimidine-4-yl)amino)-8-fluoroquinoline-5-yl)dimethylphosphine oxide (27 mg, 0.063 mmol) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 90 °C. After the reaction was complete as indicated by LCMS, the mixture was cooled, and an aqueous solution of sodium bicarbonate (100 mL) was added. The mixture was extracted with dichloromethane (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 12:1 (v / v)) to give the product (18 mg). ESI-MS (m / z): 1037.32 / 1039.32 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 12.65 (s, 1H), 10.53 (s, 1H), 8.83 (d, J = 3.7Hz, 1H), 8.58 (d, J = 12.4Hz, 1H), 8.47 (d, J = 8.8Hz, 1H), 8.42 (s,1H),8.24(s,1H),7.87(s,1H),7.71(s,1H),7.61(dd,J=8.8,4.1Hz,1H),7.47(s,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.0 Hz,1H),6.83(s,1H),3.95(s,3H),3.89(t,J=6.7Hz,2H),3.82(s,3H),3.71(s,3H),3.10-3.06(m,6H),2.74(t,J=6.7Hz,2H),2. 62-2.58(m,6H),2.33(d,J=6.8Hz,2H),2.06(s,3H),2.04(s,3H),1.80(d,J=10.9Hz,2H),1.68-1.65(m,1H),1.36-1.29(m,2H).

[0545] Example 24: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 48).

[0546] Step 1: Synthesis of 3-fluoroquinoline-6-amine

[0547] 2-Chloro-3-fluoro-6-nitroquinoline (1 g, 4.4 mmol) was added to methanol (10 mL), followed by Pd / C (500 mg, 5% Pd) and sodium bicarbonate (400 mg, 4.8 mmol). The mixture was purged three times with a hydrogen balloon, and then stirred overnight at room temperature. After LCMS analysis showed the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, the concentrate was dissolved in DCM, washed with water, dried over sodium sulfate, filtered again, and concentrated to give the product (310 mg). ESI-MS (m / z): 162.16 [M+H] + .

[0548] Step 2: Synthesis of 3-fluoro-5-iodoquinoline-6-amine

[0549] 3-Fluoroquinoline-6-amine (310 mg, 1.92 mmol) was dissolved in DMF (10 mL), and iodosuccinimide (518.4 mg, 2.3 mmol) was added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the reaction mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5 (v / v)) to give the product (145 mg). ESI-MS (m / z): 288.96 [M+H] + .

[0550] Step 3: Synthesis of (6-amino-3-fluoroquinoline-5-yl)dimethylphosphine oxide

[0551] 3-Fluoro-5-iodoquinoline-6-amine (145 mg, 0.50 mmol) was dissolved in 1,4-dioxane (10 mL), and dimethylphosphine oxide (59 mg, 0.75 mmol), palladium acetate (11.2 mg, 0.05 mmol), Xantphos (58 mg, 0.10 mmol), and potassium phosphate (214 mg, 1.0 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, filtered, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the product (99 mg). ESI-MS (m / z): 239.07 [M+H] + .

[0552] Step 4: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide

[0553] (6-Amino-3-fluoroquinoline-5-yl)dimethylphosphine oxide (95 mg, 0.40 mmol) was dissolved in n-butanol (2 mL), and 5-bromo-2,4-dichloropyrimidine (118.6 mg, 0.52 mmol) and DIEA (103 mg, 0.80 mmol) were added. The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the reaction mixture was cooled to room temperature and concentrated. The concentrate was purified by thin-layer chromatography (dichloromethane:methanol = 20:1 (v / v)) to give the product (40 mg). ESI-MS (m / z): 428.97 / 430.96 [M+H] + .

[0554] Step 5: Synthesis of Compound 48

[0555] Following the synthesis method in step 3 of Example 1, the product (25 mg) was obtained. ESI-MS (m / z): 1037.32 / 1039.32 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 12.13 (s, 1H), 10.52 (s, 1H), 8.82 (d, J = 1.98Hz, 1H), 8.43-8.42 (m, 1H), 8.26-8.24 (m, 1H), 8. 21(s,2H),7.94(s,1H),7.72(s,1H),7.61(s,1H),7.54(s,1H),7.35(d,J=12.8Hz,1H),7.09(d,J=6.9Hz,1H),6.77(s, 1H),3.92(s,3H),3.88(t,J=6.0Hz,2H),3.76(s,6H),3.11-3.06(m,4H),3.04-3.02(m,2H),2.72(t,J=6.6Hz,2H),2.5 9-2.55(m,6H),2.34-2.27(m,2H),2.01(s,3H),1.99(s,3H),1.78-1.76(m,2H),1.68-1.62(m,1H),1.34-1.27(m,2H).

[0556] Example 25: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2,3-dimethylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 49)

[0557] Step 1: Synthesis of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dimethylquinoxalin-5-yl)dimethylphosphine oxide

[0558] The synthesis method followed step 3 of Example 7 (Intermediate Preparation) to obtain the product (25 mg). ESI-MS (m / z): 440.00 / 441.99 [M+H] + .

[0559] Step 2: Synthesis of Compound 49

[0560] The synthesis method followed step 3 of Example 1, yielding the product (10 mg). ESI-MS (m / z): 1048.35 / 1050.35 [M+H] + .

[0561] Example 26: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-ethylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 50)

[0562] Step 1: Synthesis of (6-((2-chloro-5-bromopyrimidin-4-yl)amino)-2-ethylquinoxalin-5-yl)dimethylphosphine oxide

[0563] (2-Ethyl-6-aminoquinoxalo-5-yl)dimethylphosphine oxide (45 mg, 0.18 mmol) was added to n-butanol (1 mL), followed by 2,4-dichloro-5-bromopyrimidine (62 mg, 0.27 mmol) and diisopropylethylamine (70 mg, 0.54 mmol). The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 30:1 (v / v)) to give the product (80 mg). ESI-MS (m / z): 440.00 / 442.00 [M+H] + .

[0564] Step 2: Synthesis of Compound 50

[0565] 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (77 mg, 0.12 mmol) was added to isopropanol (2 mL), followed by (6-((2-chloro-5-bromopyrimidine-4-yl)amino)-2-ethylquinoxalin-5-yl)dimethylphosphine oxide (80 mg, 0.18 mmol) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 90 °C. After the reaction was complete as indicated by LCMS, the mixture was cooled, and an aqueous sodium bicarbonate solution (100 mL) was added to the mixture. The mixture was extracted with dichloromethane (3 × 50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (40 mg). ESI-MS (m / z): 1048.35 / 1050.35 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 12.54(s,1H),10.53(s,1H),8.79(s,1H),8.70(s,1H),8.38(s,1H),8.25(s,1H),8.13(s,1H),7.98 (s,1H),7.81(s,1H),7.54(s,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.1Hz,1H),6.85(s,1H),3.95(s,3H),3.89(t,J=6.7Hz ,2H),3.80(s,3H),3.77(s,3H),3.15-3.06(m,6H),2.96(q,J=7.5Hz,2H),2.74(t,J=6.7Hz,2H),2.67-2.61(m,6H),2.35(d, J=6.6Hz,2H),2.01(s,3H),1.99(s,3H),1.81(d,J=11.2Hz,2H),1.71-1.66(m,1H),1.38-1.34(m,2H),1.32(t,J=7.6Hz,3H).

[0566] Example 27: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 51)

[0567] Steps 1 to 4: Proceed according to intermediate preparation example 20.

[0568] Step 5: Synthesis of 1-(6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0569] The synthesis method followed step 1 of Example 1, except that the crude 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate was replaced with 1-(6-(piperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, yielding the product (120 mg). ESI-MS (m / z): 604.29 [M+H] + .

[0570] Step 6: Synthesis of 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0571] The synthesis method followed step 2 of Example 1, except that 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was replaced with 1-(6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazole-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyperidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, yielding the product (118 mg). ESI-MS (m / z): 574.32 [M+H] +

[0572] Step 7: Synthesis of Compound 51

[0573] The synthesis method followed step 3 of Example 1, yielding the product (30 mg). ESI-MS (m / z): 980.32 / 982.32 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 11.95 (s, 1H), 10.34 (s, 1H), 8.35-8.31 (m, 1H), 8.23 ​​(s, 1H), 8.22-8.19 (m, 3H), 8.08-8. 06(m,1H),7.94(s,1H),7.74(s,1H),7.53-7.49(m,2H),6.85(d,J=9.1Hz,1H),6.78(s,1H),3.79(s,3H),3.77(s,3 H),3.72-3.69(m,2H),3.51-3.47(m,4H),3.04(d,J=11.0Hz,2H),2.70(t,J=6.7Hz,2H),2.61-2.58(m,5H),2.48-2 .46(m,4H),2.29-2.26(m,2H),2.00(s,3H),1.98(s,3H),1.81-1.77(m,2H),1.69-1.65(m,1H),1.34-1.29(m,2H).

[0574] Example 28: Synthesis of 3-(5-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (Compound 52)

[0575] Step 1: Synthesis of tert-butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0576] Methyl 2-bromo-4-fluorobenzoate (39.50 g, 169.50 mmol) and tert-butyl piperazine-1-carboxylate (47.36 g, 254.20 mmol) were dissolved in dimethyl sulfoxide (600 mL), followed by the addition of potassium carbonate (46.85 g, 339.01 mmol). The reaction mixture was stirred at 110 °C for 12 hours. The reaction solution was poured into ice water (1.2 L) and extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed three times with water (500 mL) and once with a saturated sodium chloride aqueous solution (500 mL). The mixture was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (70.00 g). ESI-MS (m / z): 399.08 [M+H] + .

[0577] Step 2: Synthesis of 2-bromo-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)benzoic acid

[0578] 35.00 g of tert-butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate was dissolved in methanol (120 mL), water (120 mL), and tetrahydrofuran (120 mL), followed by the addition of sodium hydroxide (14.03 g, 350.63 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water (300 mL), and impurities were extracted with ethyl acetate (200 mL × 3). The aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid and then extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed once each with water (400 mL) and 400 mL with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give the product (21.00 g). ESI-MS (m / z): 385.07 [M+H] + .

[0579] Step 3: Synthesis of 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-formylbenzoic acid

[0580] 5.00 g of 2-bromo-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)benzoic acid was placed under nitrogen atmosphere and 75 mL of tetrahydrofuran was added. The reaction mixture was cooled to -78 °C, and 1.6 M methyllithium (8.1 mL, 12.98 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 30 minutes. Then, 2.5 M n-butyllithium (6.2 mL, 15.50 mmol) was added dropwise, and stirring continued for another 30 minutes. N,N-dimethylformamide (2.85 g, 38.94 mmol) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 hour. The reaction mixture was then slowly heated to 25 °C and stirred for 1 hour. The reaction mixture was then slowly quenched by pouring 30 mL of saturated ammonium chloride aqueous solution into the solution. The reaction solution was adjusted to pH 4-5 with 2N dilute hydrochloric acid, then extracted with EA (100 mL × 3). The organic phase was washed once with water (100 mL) and once with saturated sodium chloride aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with petroleum ether:ethyl acetate = 1:3 and filtered to obtain a filter cake. After drying the filter cake, the product (2.5 g) was obtained. ESI-MS (m / z): 335.15 [M+H] + .

[0581] Step 4: Synthesis of 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-(((2,6-dioxopiperidin-3-yl)amino)methyl)benzoic acid

[0582] 3-Aminopiperidine-2,6-dione hydrochloride (1.55 g, 9.44 mmol) was dissolved in methanol (50 mL), and then anhydrous sodium acetate (1.29 g, 15.73 mmol) was added. The mixture was stirred at 25 °C for 30 min. 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-carboxybenzoic acid (2.63 g, 7.87 mmol) was added to the reaction mixture, and the mixture was stirred for another 30 min. Then, sodium cyanoborohydride (0.97 g, 15.73 mmol) was added to the reaction mixture at 25 °C, and the mixture was stirred for another 2 h. LC-MS showed that the starting material disappeared and a product was formed. The reaction mixture was poured into water, and the pH was adjusted to 4-5 with 2N dilute hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate (100 mL × 3), and the organic phase was washed once with brine (50 mL). After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was then slurried with ethyl acetate: petroleum ether = 1:3 to obtain the product (3.00 g). ESI-MS (m / z): 447.22 [M+H] + .

[0583] Step 5: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperazine-1-carboxylate

[0584] 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-2-(((2,6-dioxopiperidin-3-yl)amino)methyl)benzoic acid (3.00 g) was dissolved in N,N-dimethylformamide (40 mL), followed by the sequential addition of N,N-diisopropylethylamine (2.61 g, 20.16 mmol) and 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.06 g, 8.06 mmol). After the additions were complete, the reaction was carried out at 25 °C for 2 hours. The reaction solution was poured into ice water (100 mL), then extracted three times with ethyl acetate (60 mL). The organic phase was washed three times with water (40 mL × 3), and then once with saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1 (v / v)), and then slurried with methyl tert-butyl ether (20 mL × 2) to obtain the product (0.95 g). ESI-MS (m / z): 429.21 [M+H] + .

[0585] Step 6: Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindoline-2-yl)piperidine-2,6-dione trifluoroacetate

[0586] 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester (80 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed as shown by LC-MS, the solution was concentrated to dryness under reduced pressure to give the product trifluoroacetate (80 mg). ESI-MS (m / z): 329.15 [M+H] + .

[0587] Step 7: Synthesis of 3-(5-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0588] The synthesis method followed step 1 of Example 1, yielding the product (88 mg). ESI-MS (m / z): 657.31 [M+H] + .

[0589] Step 8: Synthesis of 3-(5-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0590] The synthesis method followed step 2 of Example 1, yielding the product (75 mg). ESI-MS (m / z): 627.33 [M+H] + .

[0591] Step 9: Synthesis of Compound 52

[0592] The synthesis method followed step 3 of Example 1, yielding the product (20 mg). ESI-MS (m / z): 1033.33 / 1035.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 11.95(s,1H),10.95(s,1H),8.35-8.32(m,1H),8.26-8.18(m,4H),7.94(s,1H),7.75(s,1H ),7.55-7.51(m,2H),7.10-7.05(m,2H),6.78(s,1H),5.06(d,J=8.8Hz,1H),4.34(d,J=16.7Hz,1H),4.22(d,J=16.7 Hz,1H),3.80(s,3H),3.78(s,3H),3.07-3.02(m,2H),2.93-2.87(m,2H),2.62-2.56(m,8H),2.56-2.52(m,5H),2.41 –2.34(m,2H),2.33-2.28(m,2H),2.01(s,3H),1.99(s,3H),1.81-1.77(m,2H),1.69-1.65(m,1H),1.36-1.32(m,2H).

[0593] Example 29: Synthesis of 3-((4-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (Compound 53)

[0594] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate

[0595] 1,2-Difluoro-4-nitrobenzene (2 g, 12.6 mmol) was added to N,N-dimethylformamide (30 mL), followed by piperazine-1-carboxylic acid tert-butyl ester (2.46 g, 13.2 mmol) and diisopropylethylamine (4.9 g, 37.8 mmol). The reaction mixture was stirred at 100 °C. LC-MS showed that after the reaction was complete, the mixture was cooled, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product (4.2 g). ESI-MS (m / z): 326.14 [M+H] + .

[0596] Step 2: Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate

[0597] 4.2 g of crude 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester was added to 50 mL of ethyl acetate, followed by 4 g of aqueous palladium on carbon and 8 mL of triethylsilane. The reaction mixture was stirred at room temperature. LC-MS analysis showed that the reaction was complete. The concentrate was then purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1 (v / v)) to give the product (3.7 g). ESI-MS (m / z): 296.17 [M+H] +

[0598] Step 3: Synthesis of 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[0599] 4-(4-amino-2-fluorophenyl)piperidin-1-carboxylic acid tert-butyl ester (1 g, 3.39 mmol) was added to N,N-dimethylformamide (10 mL), followed by 3-bromopiperidin-2,6-dione (1.6 g, 8.47 mmol) and diisopropylethylamine (1.3 g, 10.1 mmol). The reaction mixture was stirred at 80 °C. LC-MS showed that after the reaction was complete, the mixture was cooled and purified using a medium-pressure preparative column (C18 column, water (0.1% formic acid) / acetonitrile = 20 / 1 to 1 / 20 (v / v)) to give the product (810 mg). ESI-MS (m / z): 407.20 [M+H] + .

[0600] Step 4: Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0601] 810 mg (2 mmol) of 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester was added to 10 mL of dichloromethane, followed by 3 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the mixture was concentrated, and the concentrate was purified by silica gel column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give the product (700 mg). ESI-MS (m / z): 307.15 [M+H] + .

[0602] Step 5: Synthesis of 3-((3-fluoro-4-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione

[0603] 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde (378 mg, 1.1 mmol) was added to tetrahydrofuran (10 mL), followed by 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (307 mg, 1 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (424 mg, 2 mmol) was added. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (100 mL) was added to the mixture, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product (330 mg). ESI-MS (m / z): 635.30 [M+H] + .

[0604] Step 6: Synthesis of 3-((4-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione

[0605] 3-((3-fluoro-4-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidin-2,6-dione (330 mg, 0.52 mmol) was added to ethyl acetate (10 mL), followed by hydrated palladium on carbon (500 mg) and triethylsilane (0.5 mL). The reaction mixture was stirred at room temperature. LC-MS showed that the reaction was complete. The concentrate was then purified by silica gel column chromatography (dichloromethane:methanol = 30:1 (v / v)) to give the product (60 mg). ESI-MS (m / z): 605.33 [M+H]+ .

[0606] Step 7: Synthesis of Compound 53

[0607] (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide (44 mg, 0.1 mmol) was added to n-butanol (2 mL), followed by 3-((4-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (60 mg, 0.1 mmol) and trifluoroacetic acid (0.1 mL). The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and an aqueous solution of sodium bicarbonate (50 mL) was added to the mixture. The mixture was extracted with dichloromethane (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (3 mg). ESI-MS (m / z): 1011.33 / 1013.33 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 11.94(s,1H),8.32(s,1H),8.23-8.19(m,4H),7.94(s,1H),7.73(s,2H),7.52(s,1H), 7.47(dd,J=15.1,2.2Hz,1H),7.23(s,1H),7.12-7.10(m,1H),7.04-7.00(m,1H),6.77(s,1H),4.63(dd,J=8.7,2 .9Hz,1H),3.79(s,3H),3.77(s,3H),3.05-3.00(m,6H),2.59-2.53(m,6H),2.43-2.34(m,3H),2.29(d,J=6.9Hz, 2H), 2.00 (s, 3H), 1.98 (s, 3H), 1.94-1.91 (m, 1H), 1.78 (d, J = 11.6Hz, 2H), 1.66-1.63 (m, 1H), 1.35-1.28 (m, 2H).

[0608] Example 30: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(diethylphosphono)-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 54)

[0609] The synthesis method was as described in Example 4, yielding a product (23 mg). ESI-MS (m / z): 1061.37 / 1063.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ12.42(s,1H),10.53(s,1H),8.51(s,1H),8.32(d,J=8.8Hz,1H),8.21(s,2H),7.95(s,1H),7.79(s,1H) ,7.58(s,1H),7.54–7.48(m,1H),7.37(d,J=5.5Hz,1H),7.36(s,1H),7.11(d,J=7.0Hz,1H),6.80(s,1H),3.95(s,3H),3.90(t,J =6.7Hz,2H),3.78(s,6H),3.11(s,4H),3.08(s,1H),2.75(t,J=6.6Hz,2H),2.62-2.64(m,2H),2.61(s,5H),2.34(d,J=6.7Hz,2H ),2.23-2.29(m,4H),1.81(d,J=11.0Hz,2H),1.69(s,1H),1.34(dd,J=26.5,15.8Hz,3H),1.24-1.26(m,2H),0.97-1.02(m,6H).

[0610] Example 31: Synthesis of 3-(5-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (Compound 55)

[0611] Step 1: Synthesis of tert-butyl 4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0612] The synthesis method follows step 1 of Example 1 for intermediate preparation, yielding the product (200 mg).

[0613] Step 2: Synthesis of 1-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine

[0614] 200 mg (0.39 mmol) of 4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in DCM (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 h. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification. ESI-MS (m / z): 415.24 [M+H] + .

[0615] Step 3: Synthesis of 3-(5-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidin-2,6-dione

[0616] The synthesis method followed step 1 of Example 4 (Intermediate Preparation), yielding the product (220 mg). ESI-MS (m / z): 792.38 [M+H] + .

[0617] Step 4: Synthesis of 3-(5-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0618] 220 mg (0.28 mmol) of 3-(5-(4-(((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidin-2,6-dione was dissolved in toluene (3 mL), and trifluoroacetic acid (2 mL) was added. The system was heated to 100 °C and reacted for 6 h. LCMS showed that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, diluted with dichloromethane, and then saturated sodium bicarbonate aqueous solution was added. The mixture was stirred and separated. The organic phase was concentrated to dryness under reduced pressure and purified by preparative TLC to give the product (65 mg). ESI-MS (m / z): 672.32 [M+H] + .

[0619] Step 5: Synthesis of 3-(5-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0620] The synthesis method followed step 2 of Example 1, yielding the product (50 mg). ESI-MS (m / z): 642.34 [M+H] + .

[0621] Step 6: Synthesis of Compound 55

[0622] The synthesis method followed step 3 of Example 1, yielding the product (20 mg). ESI-MS (m / z): 1048.34 / 1050.34 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ: 11.93(s,1H),11.07(s,1H),8.33(s,1H),8.28–8.14(m,3H),7.94(s,1H),7.74(s,1H), 7.53(s,1H),6.95(d,J=8.5Hz,1H),6.85(s,1H),6.78(s,1H),6.64(d,J=8.4Hz,1H),5.29(dd,J=12.8,5.3Hz,1H) ,3.84–3.73(m,5H),3.31(s,6H),3.11(s,3H),3.05(d,J=10.1Hz,2H),2.94–2.85(m,1H),2.73–2.65(m,1H),2.67 -2.55(m,10H),2.30(d,J=6.7Hz,2H),2.05-1.94(m,6H),1.79(d,J=11.1Hz,2H),1.67(s,1H),1.34–1.28(m,2H).

[0623] Example 32: Synthesis of 1-(4-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 56)

[0624] The synthesis method followed steps 5-7 of Example 29, yielding the product (11 mg). ESI-MS (m / z): 979.32 / 981.32 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ: 11.94 (s, 1H), 10.26 (s, 1H), 8.32 (d, J = 5.2Hz, 1H), 8.23 ​​(d, J = 12.8Hz, 3H), 7.94 (s, 1H), 7.74 (s, 1 H),7.56(s,1H),7.52(s,1H),7.16(d,J=8.9Hz,2H),6.95(d,J=9.0Hz,2H),6.78(s,1H),3.80(s,2H),3.78(s,3H),3.70(t, J=6.7Hz,2H),3.15(s,3H),3.05(d,J=11.0Hz,2H),2.69(t,J=6.7Hz,2H),2.60(d,J=2.3Hz,4H),2.52-2.56(m,4H),2.30(d ,J=6.7Hz,2H),2.01(s,3H),1.98-1.99(m,3H),1.79(d,J=11.2Hz,2H),1.67(s,1H),1.30-1.34(m,2H),1.24-1.26(m,3H).

[0625] Example 33: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 57)

[0626] Step 1: Synthesis of 5-fluoro-6-bromo-1H-indazole-3-amine

[0627] 2,5-Difluoro-4-bromobenzonitrile (2 g, 9.17 mmol) was added to n-butanol (15 mL), followed by hydrazine hydrate (4.6 g, 143.55 mmol). The reaction mixture was stirred at 120 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and water (100 mL) was added to the mixture. The mixture was extracted with ethyl acetate (3 × 100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was added to methanol (10 mL), stirred at room temperature for 30 minutes, filtered, dried, and the filter cake was collected to give the product (1.7 g). ESI-MS (m / z): 229.97 / 231.97 [M+H] + .

[0628] Step 2: Synthesis of 2-(5-fluoro-6-bromo-1H-indazol-3-yl)isoindoline-1,3-dione

[0629] 5-Fluoro-6-bromo-1H-indazole-3-amine (500 mg) was added to 1,4-dioxane (10 mL), followed by phthalic anhydride (420 mg, 2.84 mmol). The reaction mixture was stirred at 120 °C. LC-MS showed that the reaction was complete. After cooling, the mixture was concentrated and added to methanol (5 mL), and stirred at room temperature for 30 minutes. The mixture was filtered, dried, and the filter cake was collected to obtain the product (600 mg). ESI-MS (m / z): 359.97 / 361.97 [M+H] + .

[0630] Step 3: Synthesis of 2-(5-fluoro-6-bromo-1-(methyl-d3)-1H-indazol-3-yl)isoindoline-1,3-dione

[0631] 2-(5-fluoro-6-bromo-1H-indazol-3-yl)isoindoline-1,3-dione (500 mg) was added to N,N-dimethylformamide (10 mL), followed by potassium carbonate (383 mg, 2.78 mmol) and iodomethane-d3 (222 mg, 1.53 mmol). The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (100 mL) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was then filtered, dried, and the filter cake was collected to obtain the product (500 mg). ESI-MS (m / z): 377.01 / 379.01 [M+H] + .

[0632] Step 4: Synthesis of 5-fluoro-6-bromo-1-(methyl-d3)-1H-indazole-3-amine

[0633] 500 mg of 2-(5-fluoro-6-bromo-1-(methyl-d3)-1H-indazol-3-yl)isoindoline-1,3-dione was added to 10 mL of ethanol, followed by the addition of hydrazine hydrate (434 mg, 13.54 mmol). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LC-MS, 100 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:3 (v / v)) to give the product (160 mg). ESI-MS (m / z): 247.00 / 249.00 [M+H] + .

[0634] Step 5: Synthesis of 3-((5-fluoro-6-bromo-1-(methyl-d3)-1H-indazol-3-yl)amino)propionic acid

[0635] 180 mg (0.72 mmol) of 5-fluoro-6-bromo-1-(methyl-d3)-1H-indazole-3-amine was added to an aqueous solution of hydrochloric acid (2 N, 5 mL), followed by acrylic acid (105 mg, 1.47 mmol). The reaction mixture was stirred at 100 °C. LC-MS showed that after the reaction was complete, the mixture was cooled, and the pH was adjusted to 8 by adding an aqueous solution of sodium bicarbonate. Acetic acid was then added to adjust the pH to 5. The mixture was stirred at room temperature for 20 minutes, filtered, dried, and the filter cake was collected to obtain the product (190 mg). ESI-MS (m / z): 319.02 / 321.02 [M+H] + .

[0636] Step 6: Synthesis of 1-(5-fluoro-6-bromo-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0637] 180 mg of 3-((5-fluoro-6-bromo-1-(methyl-d3)-1H-indazol-3-yl)amino)propionic acid was added to acetic acid (5 mL), followed by sodium cyanate (78 mg, 1.2 mmol). The reaction mixture was stirred at 60 °C. After the starting material was consumed by LCMS, the mixture was cooled, and 5 mL of 2 N hydrochloric acid solution was added. The reaction mixture was stirred at 60 °C. After the reaction was complete by LCMS, the mixture was cooled, filtered, dried, and the filter cake was collected to give the product (110 mg). ESI-MS (m / z): 344.02 / 346.02 [M+H] + .

[0638] Step 7: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-(methyl-d3)-1H-indazol-6-yl)piperazine-1-carboxylic acid

[0639] 95 mg of 1-(5-fluoro-6-bromo-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was added to 5 mL of 1,4-dioxane, followed by piperazine-1-carboxylic acid tert-butyl ester (258 mg, 1.38 mmol), Pd2(dba)3 (51 mg, 0.056 mmol), Ruphos (52 mg, 0.112 mmol), and cesium carbonate (183 mg, 0.56 mmol). The reaction mixture was stirred at 110 °C under an argon atmosphere. After the reaction was complete as shown by LCMS, the mixture was cooled, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and then concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 15:1 (v / v)) to give the product (120 mg). ESI-MS (m / z): 450.23 [M+H] +.

[0640] Step 8: Synthesis of 1-(5-fluoro-1-(methyl-d3)-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0641] 120 mg (0.267 mmol) of 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-(methyl-d3)-1H-indazol-6-yl)piperazine-1-carboxylic acid tert-butyl ester was added to dichloromethane (5 mL), followed by trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature. LC-MS showed that the reaction was complete. The mixture was then concentrated to give the product (100 mg). ESI-MS (m / z): 350.17 [M+H] + .

[0642] Step 9: Synthesis of 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0643] 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde (138 mg) was added to tetrahydrofuran (10 mL), followed by 1-(5-fluoro-1-(methyl-d3)-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (140 mg, 0.4 mmol). The mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (170 mg, 0.8 mmol) was added. The mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (100 mL) was added to the mixture, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (210 mg). ESI-MS (m / z): 678.33 [M+H] + .

[0644] Step 10: Synthesis of 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0645] 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (210 mg, 0.31 mmol) was added to ethanol (5 mL), along with reduced iron powder (87 mg, 1.55 mmol), ammonium chloride (164 mg, 3.1 mmol), and water (3 mL). The reaction mixture was stirred at 80 °C. LCMS showed that after the reaction was complete, the temperature was lowered, the reaction solution was filtered and concentrated, and the concentrate was added to a sodium bicarbonate aqueous solution (100 mL). Extraction was performed with dichloromethane (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (100 mg). ESI-MS (m / z): 648.35 [M+H] + .

[0646] Step 11: Synthesis of Compound 57

[0647] (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide (49 mg, 0.11 mmol, intermediate 2) was added to N,N-dimethylformamide (2 mL), followed by 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-(methyl-d3)-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (64 mg, 0.1 mmol) and p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol). The reaction mixture was stirred at 120 °C. After the reaction was complete, the mixture was cooled, and water (100 mL) was added. The mixture was extracted with dichloromethane (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel thin-plate chromatography (dichloromethane:methanol = 10:1 (v / v)) to give the product (16 mg). ESI-MS (m / z): 1054.35 / 1056.35 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ11.94(s,1H),10.53(s,1H),8.33(s,1H),8.29-8.20(m,3H),7.94(s,1H),7. 74(s,1H),7.53(s,2H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.1Hz,1H),6.78(s,1H),3.89(t,J=6.7Hz, 2H),3.80(s,3H),3.77(s,3H),3.10-3.04(m,6H),2.74(t,J=6.7Hz,2H),2.60-2.57(m,9H),2.33(d,J =6.8Hz,2H),2.00(s,3H),1.98(s,3H),1.80(d,J=11.3Hz,2H),1.69-1.66(m,1H),1.35-1.32(m,2H).

[0648] Example 34: 1-(6-(4-((1-(4-((5-bromo-4-((5-(diethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 58)

[0649] The synthesis method followed step 11 of Example 33, except that (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)dimethylphosphine oxide was replaced with (6-(((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinoline-5-yl)diethylphosphine oxide (intermediate 24), yielding the product (7 mg). ESI-MS (m / z): 1079.37 / 1081.36 [M+H] + .

[0650] Example 35: (R)-1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 59)

[0651] Step 1: Synthesis of (S)-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)pyrrolidine-3-yl)methanol

[0652] 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (250 mg, 1 mmol) was added to N,N-dimethylformamide (5 mL), followed by (S)-pyrrolidine-3-ylmethanol (120 mg, 1.2 mmol) and potassium carbonate (414 mg, 3 mmol). The reaction mixture was stirred at 100 °C. After LCMS showed the reaction was complete, the mixture was cooled and added to water (100 mL). The solution was extracted with dichloromethane (3 × 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the solution was concentrated to dryness under reduced pressure to give the product (330 mg, crude product). ESI-MS (m / z): 333.15 [M+H] + .

[0653] Step 2: Synthesis of (S)-1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)pyrrolidine-3-carboxaldehyde

[0654] (S)-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)pyrrolidine-3-yl)methanol (332 mg) was added to dichloromethane (15 mL), followed by the addition of Dysmartin oxidant (848 mg, 2 mmol). The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, saturated aqueous solutions of sodium thiosulfate and sodium bicarbonate were added to the reaction mixture. The mixture was stirred at room temperature for 20 minutes and extracted with dichloromethane (3 × 50 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel thin-plate chromatography (ethyl acetate as the developing solvent) to give the product (200 mg). ESI-MS (m / z): 331.13 [M+H] + .

[0655] Step 3: Synthesis of (R)-1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0656] (S)-1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)pyrrolidine-3-carboxaldehyde (200 mg, 0.6 mmol) was added to N,N-dimethylformamide (5 mL), followed by 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (278 mg). The mixture was stirred at room temperature for 20 minutes, and then sodium triacetoxyborohydride (254 mg, 1.2 mmol) was added. The mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined and concentrated. The concentrate was purified by thin-plate chromatography (dichloromethane:methanol = 10:1, v / v) to give the product (320 mg). ESI-MS (m / z): 661.29 [M+H] + .

[0657] Step 4: Synthesis of (R)-1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0658] (R)-1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (320 mg, 0.48 mmol) was added to ethanol (10 mL), followed by water (10 mL), reduced iron powder (135 mg, 2.4 mmol), and ammonium chloride (254 mg, 4.8 mmol). The mixture was stirred at 80 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and water (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (3 x 50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product (240 mg). ESI-MS (m / z): 631.32 [M+H] + .

[0659] Step 5: Synthesis of Compound 59

[0660] (R)-1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (44 mg, 0.07 mmol) was added to N,N-dimethylformamide (3 mL), followed by (6-((5-bromo-2-chloropyrimidine-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (30 mg, 0.07 mmol, product of step 4 in Example 24) and p-toluenesulfonic acid monohydrate (27 mg, 0.14 mmol). The mixture was stirred at 120 °C. LCMS showed that after the reaction was completed and the temperature was lowered, the reaction solution was directly purified by reverse-phase chromatography under medium pressure (water (0.1% FA, v / v): acetonitrile = 19 / 1 to 1 / 19, v / v), the product phase was collected, combined and concentrated, and then purified by thin-plate chromatography (dichloromethane: methanol = 15:1, v / v) to obtain the product (15 mg). ESI-MS (m / z): 1023.30 / 1025.30 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 12.21 (s, 1H), 10.52 (s, 1H), 8.84 (s, 1H), 8.48 (d, J = 7. 9Hz,1H),8.24-8.21(m,3H),7.74(s,1H),7.67-7.63(m,1H),7.54(s,1H),7.36-7 .34(m,2H),7.09(d,J=6.9Hz,1H),6.67(s,1H),3.94(s,3H),3.89(t,J=6.6Hz,2 H),3.79(s,3H),3.78(s,3H),3.07-3.04(m,5H),3.02-2.95(m,2H),2.80-2.78(m Hz,1H),2.74(t,J=6.5Hz,2H),2.61-2.58(m,4H),2.42-2.39(m,2H),2.03(s,3H),2.01(s,3H),1.60-1.55(m,1H),1.25-1.23(m,2H).

[0661] Example 36: (S)-1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrrolidine-3-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 60)

[0662] The synthesis method was as described in Example 35, yielding a product (15 mg). ESI-MS (m / z): 1023.30 / 1025.30 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 12.21 (s, 1H), 10.53 (s, 1H), 8.84 (s, 1H), 8.49 (d, J = 8.7Hz, 1H), 8.24-8.19 (m, 3H), 7.75 ( s,1H),7.69-7.63(m,1H),7.55(s,1H),7.37(s,1H),7.35(s,1H),7.10(d,J=7.1Hz,1H),6.68(s,1H),3.94(s,3H),3 .90(t,J=6.7Hz,2H),3.80(s,3H),3.79(s,3H),3.08-3.04(m,5H),3.01-2.97(m,2H),2.81-2.79(m,1H),2.74(t,J =6.7Hz,2H),2.61-2.59(m,4H),2.41-2.38(m,2H),2.04(s,3H),2.01(s,3H),1.59-1.56(m,1H),1.26-1.24(m,2H).

[0663] Example 37: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 61)

[0664] The synthesis method followed step 5 of Example 35, yielding the product (47 mg). ESI-MS (m / z): 1036.32 / 1038.32 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ12.16(s,1H),10.52(s,1H),8.84(d,J=2.1Hz,1H),8.44(d,J=6.0Hz,1H),8.27(d,J=10.8Hz,1H),8.23(s ,2H),7.95(s,1H),7.74(s,1H),7.61(s,1H),7.55(s,1H),7.34(d,J=12.7Hz,1H),7.08(d,J=7.1Hz,1H),6.78(s,1H),3.94(s,3H) ,3.89(t,J=6.7Hz,2H),3.79(s,3H),3.78(s,3H),3.45(d,J=11.4Hz,2H),3.04(d,J=10.9Hz,2H),2.78-2.67(m,4H),2.59(t,J=1 1.0Hz,2H),2.03(s,3H),2.01(s,3H),1.81(d,J=11.3Hz,2H),1.73(d,J=10.8Hz,2H),1.58(s,1H),1.51(s,1H),1.4-1.24(m,6H).

[0665] Example 38: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 62)

[0666] Step 1: Synthesis of 1-bromo-2-chloro-4-cyclobutoxy-5-nitrobenzene

[0667] 1-Bromo-2-chloro-4-fluoro-5-nitrobenzene (500 mg, 2 mmol) was added to N,N-dimethylformamide (5 mL), followed by cyclobutanol (151 mg, 2.1 mmol) and cesium carbonate (1.3 g, 4 mmol). The mixture was stirred at 70 °C. After the reaction was complete as shown by LC-MS, the mixture was cooled, and water (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic phases were concentrated. The concentrate was purified by column chromatography (using n-hexane as eluent) to give the product (470 mg). ESI-MS (m / z): 305.95 / 307.95 [M+H] + .

[0668] Step 2: Synthesis of 1-(6-(4-((1-(2-bromo-5-cyclobutoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0669] 1-Bromo-2-chloro-4-cyclobutoxy-5-nitrobenzene (470 mg, 1.5 mmol) was added to N,N-dimethylformamide (5 mL), followed by 1-(5-fluoro-1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (665 mg, 1.5 mmol) and potassium carbonate (621 mg, 4.5 mmol). The mixture was stirred at 80 °C. After the reaction was complete as indicated by LCMS, the mixture was cooled, and water (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (3 × 50 mL), and the organic phases were combined and concentrated. The concentrate was added to a mixed solvent (10 mL, ethyl acetate: n-hexane = 1:10, v / v), stirred at room temperature for 20 minutes, filtered, and the filter cake was collected, dried, and the product (280 mg) was obtained. ESI-MS(m / z):713.21 / 715.21[M+H] + .

[0670] Step 3: Synthesis of 1-(6-(4-((1-(5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0671] 1-(6-(4-((1-(2-bromo-5-cyclobutoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (280 mg, 0.39 mmol) was added to 1,4-dioxane (5 mL), followed by (1-methyl-1H-pyrazol-4-yl)boric acid (99 mg, 0.79 mmol), Pd(dppf)Cl2 (28 mg, 0.039 mmol), potassium carbonate (109 mg, 0.79 mmol), and water (2 mL). The reaction mixture was stirred under a nitrogen atmosphere at 100 °C. LCMS showed that after the reaction was complete, the mixture was cooled and concentrated. The concentrate was used directly in the next reaction without further processing. ESI-MS (m / z): 715.34 [M+H] + .

[0672] Step 4: Synthesis of 1-(6-(4-((1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0673] Crude 1-(6-(4-((1-(5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg) was added to ethanol (10 mL), followed by reduced iron powder (109 mg, 1.95 mmol), ammonium chloride (207 mg, 3.9 mmol), and water (10 mL). The reaction mixture was stirred at 80 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and water (100 mL) was added to the mixture. The mixture was extracted with dichloromethane (3 x 50 mL). The combined organic phases were concentrated, and the concentrate was purified by thin-plate chromatography (dichloromethane:methanol = 15:1, v / v) to give the product (60 mg). ESI-MS (m / z): 685.37 [M+H] + .

[0674] Step 5: Synthesis of Compound 62

[0675] 1-(6-(4-((1-(4-amino-5-cyclobutoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (60 mg, 0.088 mmol) was added to N,N-dimethylformamide (3 mL), followed by (6-((5-bromo-2-chloropyrimidine-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (45 mg, 0.11 mmol, product of step 4 in Example 24) and p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol). The mixture was stirred at 120 °C. LCMS showed that after the reaction was completed and the temperature was lowered, the reaction solution was directly purified by reverse-phase chromatography under medium pressure (water (0.1% FA, v / v): acetonitrile = 19 / 1 to 1 / 19, v / v), the product phase was collected, combined and concentrated, and then purified by silica gel thin-plate chromatography (dichloromethane: methanol = 15:1, v / v) to obtain the product (15 mg). ESI-MS (m / z): 1077.35 / 1079.35 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 12.17 (s, 1H), 10.55 (s, 1H), 8.84 (d, J = 2.1Hz, 1H), 8.44 (d, J = 7.3Hz, 1H), 8.28 (d, J = 11.6Hz, 1H), 8.25 (s, 1H), 8.16 (b r,1H),7.93(s,1H),7.71(s,1H),7.59(s,2H),7.36(d,J=12.7Hz,1H),7 .11(d,J=6.6Hz,1H),6.58(s,1H),4.71-4.65(m,1H),3.94(s,3H),3.89( t,J=6.7Hz,2H),3.77(s,3H),3.14-3.07(m,4H),3.03-3.01(m,2H),2.7 4(t,J=6.6Hz,2H),2.61-2.53(m,4H),2.38-2.31(m,4H),2.04(s,3H),2. 01(s,3H),2.00-1.97(m,2H),1.79-1.77(m,2H),1.74-1.69(m,1H),1.6 7-1.63(m,1H),1.61-1.57(m,1H),1.35-1.32(m,2H),0.89-0.80(m,2H).

[0676] Example 39: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-cyclopropoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 63)

[0677] The synthesis method was as described in Example 38, yielding a product (16 mg). ESI-MS (m / z): 1063.33 / 1065.33 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 12.17 (s, 1H), 10.55 (s, 1H), 8.85 (s, 1H), 8.43 (d, J = 8.6Hz, 1H), 8.27 (d, J = 10.9Hz, 1H), 8.23 ​​(s, 1H), 8 .16(s,1H),7.97(s,1H),7.75(s,1H),7.56-7.51(m,2H),7.36(d,J=12.8Hz,1H),7.11(d,J=6.9Hz,1H),7.05(s,1H),3.94(s,3H) ,3.89(t,J=6.7Hz,2H),3.85-3.83(m,1H),3.79(s,3H),3.10-3.06(m,6H),2.74(t,J=6.6Hz,2H),2.61-2.54(m,6H),2.33-2.31( m,2H),2.03(s,3H),2.01(s,3H),1.80-1.78(m,2H),1.69-1.65(m,1H),1.36-1.30(m,2H),0.86-0.81(m,2H),0.75-0.71(m,2H).

[0678] Example 40: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 64)

[0679] Step 1: Synthesis of 1-fluoro-5-methoxy-4-nitro-2-vinylbenzene

[0680] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (500 mg, 2 mmol) was added to 1,4-dioxane (5 mL), followed by potassium vinyltrifluoroborate (536 mg, 4 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), potassium carbonate (550 mg, 4 mmol), and water (2 mL). The mixture was stirred under a nitrogen atmosphere at 100 °C. LC-MS showed that the reaction was complete. After cooling, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product (400 mg). ESI-MS (m / z): 198.05 [M+H] + .

[0681] Step 2: Synthesis of (1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methanol

[0682] 1-Fluoro-5-methoxy-4-nitro-2-vinylbenzene (400 mg) was added to N,N-dimethylformamide (10 mL), followed by piperidin-4-ylmethanol (253 mg, 2.2 mmol) and potassium carbonate (828 mg, 6 mmol). The reaction mixture was stirred at 100 °C. LC-MS showed that the reaction was complete. After cooling, water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined and concentrated to dryness under reduced pressure to give the product (380 mg). ESI-MS (m / z): 293.14 [M+H] + .

[0683] Step 3: Synthesis of 1-(5-methoxy-4-nitro-2-vinylphenyl)piperidine-4-carboxaldehyde

[0684] 380 mg of 1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methanol was added to 20 mL of dichloromethane, followed by the addition of Dysmartin oxidant (1.7 g, 4 mmol). The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LC-MS, saturated aqueous solutions of sodium thiosulfate and sodium bicarbonate were added. The reaction mixture was stirred at room temperature for 20 minutes. After separation, the aqueous phase was extracted with dichloromethane (3 × 50 mL). The combined organic phases were concentrated, and the concentrate was purified by column chromatography (ethyl acetate: n-hexane = 1:4, v / v) to give the product (200 mg). ESI-MS (m / z): 291.13 [M+H] + .

[0685] Step 4: Synthesis of 1-(5-fluoro-6-(4-((1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0686] 1-(5-methoxy-4-nitro-2-vinylphenyl)piperidine-4-carboxaldehyde (200 mg, 0.69 mmol) was added to N,N-dimethylformamide (5 mL), followed by 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (317 mg). The reaction mixture was stirred at room temperature for 20 minutes, then sodium triacetoxyborohydride (293 mg, 1.38 mmol) was added, and the reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, water (50 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was then filtered, the filter cake was collected and dried to obtain the product (320 mg). ESI-MS (m / z): 621.29 [M+H] + .

[0687] Step 5: Synthesis of 1-(6-(4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0688] 320 mg of 1-(5-fluoro-6-(4-((1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was added to 80 mL of ethyl acetate, followed by 5 mL of dichloromethane, 5 mL of methanol, 200 mg of palladium on carbon, and 10 mL of triethylsilane. The reaction mixture was stirred at room temperature. After the reaction was complete as shown by LCMS, the palladium on carbon was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to give 145 mg of the product. ESI-MS (m / z): 593.33 [M+H] + .

[0689] Step 6: Synthesis of Compound 64

[0690] 1-(6-(4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (65 mg, 0.11 mmol) was added to N,N-dimethylformamide (3 mL), followed by (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (52 mg, 0.12 mmol, product of step 4 in Example 24) and p-toluenesulfonic acid monohydrate (31 mg, 0.16 mmol). The reaction mixture was stirred at 120 °C. LCMS showed that after the reaction was completed and the temperature was lowered, the reaction solution was directly purified by reverse-phase chromatography under medium pressure (water (0.1% FA, v / v): acetonitrile = 19 / 1 to 1 / 19, v / v), the product phase was collected, combined and concentrated, and then purified by thin-plate chromatography (dichloromethane: methanol = 15:1, v / v) to obtain the product (17 mg). ESI-MS (m / z): 985.31 / 987.31 [M+H] + , 1 H NMR (600MHz, DMSO-d6) δ: 11.56 (s, 1H), 10.55 (s, 1H), 8.94 (d, J = 2.0Hz, 1H), 8.64 (d, J = 10.7Hz, 1H), 8.30 (br, 1H), 8.25 (s, 1H),8.02(d,J=9.1Hz,1H),8.00(s,1H),7.37(s,1H),7.35(s,1H),7.12(d,J=6.7Hz,1H),6.74(s,1H),3.95(s,3H),3.89(t, J=6.6Hz,2H),3.76(s,3H),3.13-3.05(m,4H),2.90-2.88(m,2H),2.74(t,J=6.5Hz,2H),2.66-2.58(m,6H),2.29-2.28(m,2H ),2.24-2.18(m,2H),2.00(s,3H),1.97(s,3H),1.82-1.80(m,2H),1.69-1.65(m,1H),1.27-1.26(m,2H),0.73-0.67(m,3H).

[0691] Example 41: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-2-cyclopropyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 65)

[0692] Step 1: Synthesis of 1-cyclopropyl-2-fluoro-4-methoxy-5-nitrobenzene

[0693] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (500 mg, 2 mmol) was added to 1,4-dioxane (5 mL), followed by cyclopropylboronic acid (516 mg, 6 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), potassium carbonate (552 mg, 4 mmol), and water (2 mL). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that after the reaction was complete, the mixture was cooled, and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL), and the organic phases were combined and concentrated. The concentrate was purified by column chromatography (ethyl acetate: n-hexane = 1:10, v / v) to give the product (330 mg). ESI-MS (m / z): 212.06 [M+H] + .

[0694] Step 2: Synthesis of 1-(6-(4-((1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0695] 1-Cyclopropyl-2-fluoro-4-methoxy-5-nitrobenzene (100 mg, 0.47 mmol) was added to N,N-dimethylformamide (5 mL), followed by 1-(5-fluoro-1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (261 mg, 0.47 mmol) and potassium carbonate (195 mg, 1.41 mmol). The reaction mixture was stirred at 100 °C. LC-MS showed that the reaction was complete. After cooling, the reaction mixture was concentrated. The product was not further purified and was used directly in the next reaction. ESI-MS (m / z): 635.30 [M+H] + .

[0696] Step 3: Synthesis of 1-(6-(4-((1-(4-amino-2-cyclopropyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0697] 300 mg of crude 1-(6-(4-((1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was added to 10 mL of ethanol, followed by reduced iron powder (132 mg, 2.35 mmol), ammonium chloride (249 mg, 4.7 mmol), and water (10 mL). The mixture was stirred at 80 °C. LCMS showed that the reaction was complete. After cooling, 100 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined and concentrated. The concentrate was purified by thin-plate chromatography (dichloromethane:methanol = 20:1, v / v) to give the product (46 mg). ESI-MS (m / z): 605.33 [M+H] + .

[0698] Step 4: Synthesis of Compound 65

[0699] 1-(6-(4-((1-(4-amino-2-cyclopropyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (46 mg, 0.076 mmol) was added to N,N-dimethylformamide (3 mL), followed by (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (39 mg, 0.091 mmol, product of step 4 in Example 24) and p-toluenesulfonic acid monohydrate (17 mg, 0.091 mmol). The reaction mixture was stirred at 120 °C. LCMS showed that after the reaction was completed and the temperature was lowered, the reaction solution was directly purified by reverse-phase chromatography under medium pressure (water (0.1% FA, v / v): acetonitrile = 19 / 1 to 1 / 19, v / v), the product phase was collected, combined and concentrated, and then purified by thin-plate chromatography (dichloromethane: methanol = 15:1, v / v) to obtain the product (17 mg). ESI-MS (m / z): 997.31 / 999.31 [M+H] + , 1H NMR (600MHz, DMSO-d6) δ: 11.96 (s, 1H), 10.55 (s, 1H), 8.89 (d, J = 2.0Hz, 1H), 8.41-8.36 (m, 2H), 8.21 (s, 1H), 8.11 (br, 1H), 7 .95(br,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.84(br,1H),6.70(s,1H),3.95(s,3H),3.89(t,J=6.6Hz,2H),3 .75(s,3H),3.22-3.21(m,2H),3.15-3.06(m,4H),2.74(t,J=6.6Hz,2H),2.66(t,J=10.9Hz,2H),2.62-2.54(m,4H),2.30-2. 29(m,2H),2.03-2.01(m,7H),1.86-1.84(m,2H),1.74-1.67(m,1H),1.35-1.30(m,2H),0.67-0.57(m,2H),0.30-0.21(m,2H).

[0700] Example 42: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 66)

[0701] Step 1: Synthesis of (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide

[0702] In a 50 mL reaction flask, (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (300 mg, 0.70 mmol, product from step 4 of Example 24), 4-fluoro-2-methoxy-5-nitroaniline (143 mg, 0.77 mmol), p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol), and n-butanol (10 mL) were added sequentially, and the reaction was carried out at 120 °C for 6 h. LC-MS analysis showed that the reaction was complete. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to obtain the product (348 mg). ESI-MS (m / z): 579.03 / 581.03 [M+H] + .

[0703] Step 2: Synthesis of (6-((5-bromo-2-((4-(4-(hydroxymethyl)piperidin-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide

[0704] In a 50 mL reaction flask, (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (120 mg, 0.21 mmol), 4-hydroxymethylpiperidine (30 mg, 0.25 mmol), potassium carbonate (87 mg, 0.62 mmol), and DMF (5 mL) were added and stirred at 80 °C for 2 h. LC-MS analysis showed the reaction was complete. The mixture was extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the product (155 mg). ESI-MS (m / z): 674.12 / 676.12 [M+H] + .

[0705] Step 3: Synthesis of 1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)piperidine-4-carboxaldehyde

[0706] In a 25 mL reaction flask, (6-((5-bromo-2-((4-(4-(hydroxymethyl)piperidin-1-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide (155 mg, 0.23 mmol) and DCM (5 mL) were added. While stirring, Dys-Martin reagent (195 mg, 0.46 mmol) was added, and the reaction was carried out at room temperature for 1 h. LC-MS analysis showed the reaction was complete. The reaction was quenched with sodium bicarbonate aqueous solution, extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the product (99 mg). ESI-MS (m / z): 672.11 / 674.10 [M+H] + .

[0707] Step 4: Synthesis of Compound 66

[0708] In a 25 mL reaction flask, 40 mg of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate and 5 mL of DMF were added. After adjusting the pH to 4-5 with acetic acid, the mixture was stirred for 10 min. Then, 70 mg (0.10 mmol) of 1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidine-2-yl)amino)-5-methoxy-2-nitrophenyl)piperidine-4-carboxaldehyde (0.10 mmol) was added. After stirring at room temperature for 30 min, sodium triacetoxyborohydride (0.31 mmol) was added, and the mixture was reacted at room temperature for 1 h. LCMS analysis showed the reaction was complete. Extraction was performed with sodium bicarbonate aqueous solution and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by thin-layer chromatography (DCM:MeOH = 20:1) to give the product (37 mg). ESI-MS (m / z): 1002.27 / 1004.26 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ12.52(s,1H),10.53(s,1H),8.98(s,1H),8.90(s,1H),8.68(d,J=6.2Hz,1H),8.53(d,J=10. 8Hz,1H),8.28(d,J=9.2Hz,1H),7.37(d,J=12.8Hz,1H),7.12(d,J=7.0Hz,1H),6.83(s,1H),5.76(s,1H),4.08(s,3H) ,3.95(s,3H),3.90(t,J=6.6Hz,2H),3.42(d,J=10.2Hz,2H),3.12(s,4H),3.04(t,J=10.7Hz,2H),2.75(t,J=6.6Hz,2 H), 2.62 (s, 4H), 2.34 (s, 2H), 2.09 (s, 3H), 2.07 (s, 3H), 1.88 (d, J = 11.1Hz, 2H), 1.81 (s, 1H), 1.40 (d, J = 10.7Hz, 2H).

[0709] Example 43: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 67)

[0710] The synthesis method followed step 6 of Example 40, replacing intermediate 23 with (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide to obtain the product (15 mg). ESI-MS (m / z): 982.33 / 984.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ12.53(s,1H),10.52(s,1H),8.79-8.74(m,2H),8.25-8.24(m,2H),7.84(d,J=9.2Hz,1H) ,7.41-7.34(m,2H),7.11(d,J=7.0Hz,1H),6.82(s,1H),3.95(s,3H),3.89(t,J=6.7Hz,2H),3.77(s,3H),3.14-3. 07(m,4H),3.00-2.98(m,2H),2.75-2.71(m,4H),2.68(s,3H),2.64-2.56(m,4H),2.46-2.44(m,2H),2.32-2.31( m,2H),2.02(s,3H),2.00(s,3H),1.86-1.85(m,2H),1.73-1.70(m,1H),1.35-1.32(m,2H),0.95(t,J=6.5Hz,3H).

[0711] Example 44: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 68)

[0712] Step 1: Synthesis of 1-bromo-2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)benzene

[0713] 4-Bromo-5-fluoro-2-nitrophenol (1 g, 4.2 mmol) was added to N,N-dimethylformamide (50 mL), followed by cesium carbonate (4.1 g, 12.6 mmol) and 2,2,2-trifluoroethyl trifluorosulfonate (1.47 g, 6.3 mmol). The mixture was stirred at 50 °C. LC-MS showed that the reaction was complete. After cooling, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and concentrated to dryness under reduced pressure to give the product (1.2 g). ESI-MS (m / z): 317.93 / 319.93 [M+H] + .

[0714] Step 2: Synthesis of 4-(2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)phenyl)-1-methyl-1H-pyrazole

[0715] 1-Bromo-2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)benzene (1.2 g, 3.8 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (0.96 g, 7.6 mmol) were added to 1,4-dioxane (10 mL), followed by Pd(dppf)Cl2 (278 mg, 0.38 mmol), potassium carbonate (1.05 g, 7.6 mmol), and water (5 mL). The mixture was stirred at 100 °C under a nitrogen atmosphere. LC-MS showed that the reaction was complete. After cooling, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were concentrated, and the concentrate was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:5, v / v) to give the product (760 mg). ESI-MS (m / z): 320.06 [M+H] +

[0716] Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(4-((1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0717] 4-(2-fluoro-5-nitro-4-(2,2,2-trifluoroethoxy)phenyl)-1-methyl-1H-pyrazole (344 mg, 1.08 mmol) was added to 2 mL of N,N-dimethylformamide, followed by 200 mg (0.36 mmol) of 1-(5-fluoro-1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione and potassium carbonate (149 mg, 1.08 mmol). The mixture was stirred at 100 °C. LCMS showed that the reaction was complete. After cooling, the mixture was concentrated to give a crude product (700 mg). The product was not further purified and was used directly in the next reaction. ESI-MS (m / z): 743.30 [M+H] +

[0718] Step 4: Synthesis of 1-(6-(4-((1-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0719] Crude 1-(5-fluoro-1-methyl-6-(4-(((1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitro-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (700 mg) was added to ethanol (10 mL), followed by reduced iron powder (500 mg), ammonium chloride (500 mg), and water (5 mL). The mixture was stirred at 80 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and water (100 mL) was added. The mixture was extracted with dichloromethane (3 x 50 mL), and the organic phases were combined and concentrated. The concentrate was purified by thin-plate chromatography (dichloromethane:methanol = 20:1, v / v) to give the product (130 mg). ESI-MS (m / z): 713.32 [M+H] +

[0720] Step 5: Synthesis of Compound 68

[0721] 1-(6-(4-((1-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)-5-(2,2,2-trifluoroethoxy)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (59 mg, 0.083 mmol) was added to N,N-dimethylformamide (2 mL), followed by (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinoxalin-5-yl)dimethylphosphine oxide (42 mg, 0.1 mmol, intermediate 23) and p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol). The mixture was stirred at 120 °C. LCMS showed that after the reaction was completed and the temperature was lowered, the reaction solution was directly purified by reverse-phase chromatography under medium pressure (water (0.1% FA, v / v): acetonitrile = 19 / 1 to 1 / 19, v / v). The product phases were collected, combined, concentrated, and then purified by silica gel thin-plate chromatography (dichloromethane: methanol = 15:1, v / v) to obtain the product (17 mg). ESI-MS (m / z): 1102.33 / 1104.33 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ:12.54(s,1H),10.52(s,1H),8.76(s,1H),8.68(br,1H),8.46(s,1H),8.25(s,1H),8.04(s,1H),7 .83(s,1H),7.54(s,1H),7.49(br,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.94(s,1H),4.70(q,J=8.8Hz,2H),3 .94(d,J=11.9Hz,3H),3.90(t,J=5.9Hz,2H),3.81(d,J=14.3Hz,3H),3.10-3.08(m,6H),2.74(t,J=6.6Hz,2H),2.65(s,3H) ,2.61-2.60(m,6H),2.35-2.34(m,2H),2.01(s,3H),1.98(s,3H),1.82-1.80(m,2H),1.71-1.67(m,1H),1.39-1.35(m,2H).

[0722] Example 45: Synthesis of 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 69)

[0723] The synthesis method was performed according to step 4 of Example 41, yielding the product (47 mg). ESI-MS (m / z): 1033.34 / 1035.34 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ12.56(s,1H),10.53(s,1H),8.77(s,2H),8.36(s,1H),8.25(s,1H),8.00(s,1H),7.80(s,1H),7.58(s,1H ),7.51(s,1H),7.35(d,J=12.6Hz,1H),7.09(d,J=6.8Hz,1H),6.84(s,1H),3.95(s,3H),3.92–3.87(m,2H),3.79(d,J=10.8Hz,6H) ,3.46(d,J=10.6Hz,2H),3.09(d,J=9.5Hz,2H),2.78–2.72(m,2H),2.72–2.67(m,2H),2.66(s,2H),2.55(s,3H),2.02(s,3H),2.00 (s,3H),1.83(d,J=10.8Hz,2H),1.75(d,J=10.5Hz,2H),1.57(d,J=31.4Hz,2H),1.37(d,J=11.0Hz,2H),1.34(s,2H),1.24(s,2H).

[0724] Example 46: Synthesis of N-(5-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxyphenyl)acetamide (Compound 70)

[0725] Step 1: Synthesis of 1-(6-(4-((1-(2-amino-4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0726] In a 25 mL reaction flask, 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (221 mg, 0.22 mmol, compound 66), iron powder (62 mg, 1.11 mmol), ammonium chloride (60 mg, 1.12 mmol), and ethanol:water (5:1, 6 mL) were added and stirred at 80 °C for 3 h. LCMS analysis showed that the reaction was complete. The mixture was filtered, concentrated to dryness under reduced pressure, extracted with water and dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the product (129 mg). ESI-MS(m / z):972.29 / 974.92[M+H] + .

[0727] Step 2: Synthesis of Compound 70

[0728] In a 25 mL reaction flask, 1-(6-(4-((1-(2-amino-4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (129 mg, 0.13 mmol) and DCM (5 mL) were added. Triethylamine (27 mg, 0.27 mmol) was then added, followed by stirring, and acetic anhydride (21 mg, 0.206 mmol). The reaction was carried out at room temperature for 1 h. LCMS analysis showed the reaction was complete. The mixture was concentrated to dryness under reduced pressure and purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain the product (27 mg). ESI-MS(m / z):1014.30 / 1016.30[M+H] + . 1H NMR(600MHz, DMSO-d6)δ:12.14(s,1H),10.53(s,1H),8.88(d,J=2.3Hz,1H),8.61(s,1H),8.46(d,J=6.2Hz,1H),8.32(d,J=10.8Hz ,1H),8.25(s,1H),8.23(s,1H),7.98(s,1H),7.94(d,J=9.0Hz,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=6.9Hz,1H),6.82(s,1H),3. 95(s,3H),3.90(t,J=6.7Hz,2H),3.78(s,3H),3.11(s,4H),2.98(d,J=10.3Hz,2H),2.74(t,J=6.7Hz,2H),2.67(t,J=10.9Hz,2H), 2.60(s,4H),2.32(d,J=6.1Hz,2H),2.04(s,3H),2.01(s,3H),1.98(s,3H),1.84(d,J=11.3Hz,2H),1.71(s,1H),1.38-1.48(m,2H).

[0729] Example 47: 1-(6-((1S,4S)-5-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 71)

[0730] Step 1: Synthesis of (1S,4S)-5-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0731] 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (500 mg, 1.5 mmol) was added to dioxane (30 mL), followed by (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (349 mg, 1.76 mmol), RuPhos-Pd-G2 (155 mg, 0.2 mmol), and cesium carbonate (975 mg, 3 mmol). The mixture was stirred at 100 °C. After the reaction was complete as shown by LCMS, the mixture was cooled, and the reaction solution was added to water (100 mL). The mixture was extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated and purified by column chromatography (methanol:dichloromethane = 50:1-25:1) to obtain the product (550 mg). ESI-MS (m / z): 459.20 [M+H] + .

[0732] Step 2: Synthesis of 1-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0733] (1S,4S)-5-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (550 mg, 1.2 mmol) was added to a solution of hydrogen chloride in ethyl acetate (15 mL) and stirred at room temperature. After the reaction was complete as shown by LCMS, the solution was concentrated to dryness under reduced pressure to give the hydrochloride salt of the product (420 mg). ESI-MS (m / z): 359.13 [M+H] + .

[0734] Step 3: Synthesis of 1-(5-fluoro-6-((1S,4S)-5-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0735] The hydrochloride product obtained in step 2 (420 mg) was added to N,N-dimethylformamide (20 mL), followed by 1-(5-methoxy-2-(2-methyl-2H-imidazol-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde (470 mg, 1.4 mmol). The mixture was stirred at room temperature for 20 minutes, then sodium triacetoxyborohydride (381 mg, 1.8 mmol) was added, and the mixture was stirred at room temperature. After LCMS analysis showed the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic phases were concentrated, and the concentrate was purified by thin-plate chromatography (dichloromethane:methanol = 10:1, v / v) to obtain the product (350 mg). ESI-MS (m / z): 687.29 [M+H] + .

[0736] Step 4: Synthesis of 1-(6-((1S,4S)-5-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0737] 1-(5-fluoro-6-((1S,4S)-5-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (350 mg, 0.51 mmol) was added to ethanol (10 mL), followed by water (10 mL), reduced iron powder (134 mg, 2.4 mmol), and ammonium chloride (250 mg, 4.67 mmol). The mixture was stirred at 80 °C. LC-MS showed that after the reaction was complete, the temperature was lowered, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product (220 mg). ESI-MS (m / z): 657.32 [M+H] + .

[0738] Step 5: Synthesis of Compound 71

[0739] 1-(6-((1S,4S)-5-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 0.1 mmol) was added to n-butanol (10 mL), followed by (6-((5-bromo-2-chloropyrimidine-4-yl)amino)-2-methylquinoxalin-5-yl)dimethylphosphine oxide (64 mg, 0.15 mmol) and trifluoroacetic acid (2 mL). The mixture was stirred at 120 °C. LCMS showed that after the reaction was complete, the temperature was lowered, the solvent was removed under reduced pressure, and the crude product was purified by thin-plate chromatography (dichloromethane:methanol = 15:1, v / v) to give the product (22 mg). ESI-MS (m / z): 1046.30 / 1048.30 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ:12.56(s,1H),10.52(s,1H),8.76(s,2H),8.35(s,1H ),8.25(s,1H),7.98(s,1H),7.77(s,1H),7.58(s,1H),7.48(s,1H),7.31(d,J= 13.8Hz,1H),6.81(s,1H),6.70(d,J=6Hz,1H),4.40(s,1H),3.90-3.89(m,5H), 3.79(s,3H),3.76(s,3H),3.59-3.58(m,1H),3.53-3.52(m,1H),3.36-23.35(m 1H),3.08-3.04(m,2H),2.96-2.94(m,1H),2.78-2.73(m,3H),2.63(s,3H),2.60-2.55(m,2H),2.4 8-2.45(m,2H),2.02(s,3H),1.99(s,3H),1.90-1.75(m,4H),1.48-1.40(m,1H),1.31-1.25(m,2H).

[0740] Example 48: 1-(6-((1R,4R)-5-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-2-methylquinoxalin-6-yl)amino)pyrimidin-2-yl)amino)5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 72)

[0741] The synthesis method was the same as in Example 47, except that (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in step 1 was replaced with (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, yielding the product (20 mg). ESI-MS (m / z): 1046.30 / 1048.30 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ:12.56(s,1H),10.52(s,1H),8.76(s,2H),8.35(s,1H ),8.25(s,1H),7.98(s,1H),7.77(s,1H),7.58(s,1H),7.48(s,1H),7.31(d,J= 13.8Hz,1H),6.81(s,1H),6.70(d,J=6Hz,1H),4.40(s,1H),3.90-3.89(m,5H), 3.79(s,3H),3.76(s,3H),3.59-3.58(m,1H),3.53-3.52(m,1H),3.36-23.35(m 1H),3.08-3.04(m,2H),2.96-2.94(m,1H),2.78-2.73(m,3H),2.63(s,3H),2.60-2.55(m,2H),2.4 8-2.45(m,2H),2.02(s,3H),1.99(s,3H),1.89-1.75(m,4H),1.48-1.40(m,1H),1.31-1.25(m,2H).

[0742] Example 49: 1-(6-(4-((1-(4-((5-bromo-4-((5-(dimethylphosphono)-3-fluoro-2-methylquinoline-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione (Compound 85)

[0743] The synthesis method followed step 6 of Example 40, except that (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoroquinoline-5-yl)dimethylphosphine oxide was replaced with intermediate 2 to obtain the product (24 mg). ESI-MS (m / z): 999.33 / 1001.33 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ:11.29(s,1H),10.52(s,1H),8.64(s,1H),8.29-8.14(m,2H),7.94(s,2H), 7.41-7.29(m,2H),7.11(d,J=7.1Hz,1H),6.73(s,1H),3.94(s,3H),3.89(t,J=6.7Hz,2H),3.76(s,3 H),3.10(s,4H),2.88(d,J=9.5Hz,2H),2.74(t,J=6.6Hz,2H),2.69-2.54(m,9H),2.29(d,J=6.8Hz, 2H), 2.19 (s, 2H), 1.96 (s, 3H), 1.94 (s, 3H), 1.81 (d, J = 11.2Hz, 2H), 1.67 (s, 1H), 1.32-1.20 (m, 4H).

[0744] Example 50: N-(5-((5-bromo-4-((5-(dimethylphosphono)-3-fluoroquinoline-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methoxyphenyl)acrylamide (Compound 111)

[0745] The synthesis method was the same as step 2 of Example 46, except that acetic anhydride was replaced with acryloyl chloride, yielding the product (15 mg). ESI-MS (m / z): 1026.30 / 1028.30 [M+H] + .

[0746] Bioactivity

[0747] Reference compound:

[0748] Control compound 1 and control compound 2 are compound 106 in patent WO2022228547A1 and compound 115 in Example 1 of patent WO2022194269A1, respectively. The structures of the two control compounds are as follows:

[0749] Experimental Example 1: Degradation of EGFR protein in H1975-EGFR-L858R / T790M / C797S cells based on the HiBiT method

[0750] 1. Cell lines

[0751] Cell line source: Shanghai Runnuo Biotechnology Co., Ltd.

[0752] Cell type: H1975-EGFR-L858R / T790M / C797S-HiBiT

[0753] 2. Test Methods

[0754] Cells were collected, resuspended in complete culture medium, counted, and seeded into 384-well plates at 10,000 cells per well. Different concentrations of the compound were added to each well (starting at 3 μM, 10 concentrations, 1:3 dilution, 2 replicates). A control group with cells supplemented with DMSO and a blank control group with cell culture medium were also included. The DMSO concentration was 0.1%. The cell culture plates were incubated at 37°C in a 5% CO2 incubator for 16 hours.

[0755] Nano-Glo HiBiT assay solution was prepared by mixing Nano-Glo HiBiT Lytic Buffer, Substate, and Protein in a ratio of 100:2:1. 20 μL of the Nano-Glo HiBiT assay solution was added to each well, and the mixture was shaken at 300 rpm on a shaker and incubated at room temperature in the dark for 10 minutes. Detection was performed using an Envision microplate reader, and the data were read to calculate the protein degradation rate.

[0756] Degradation rate % = (1 - (positive control - compound pores) / (positive control - negative control)) * 100%.

[0757] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)).

[0758] After fitting the curve using the four-parameter method with Prism software, the DC value was calculated. 50 .

[0759] Table 2. Degradation activity of the compounds of the present invention against H1975-EGFR-L858R / T790M / C797S cells.

[0760] The experimental results show that the compound of the present invention has a good EGFR protein degradation effect on H1975-EGFR-L858R / T790M / C797S cells.

[0761] Experimental Example 2: Inhibition of Different Cell Proliferation Based on MTT Assay

[0762] 1. Cell lines

[0763] Cell line source: Nanjing Kebai Biotechnology Co., Ltd.

[0764] Cell types: H1975-EGFR-L858R / T790M / C797S (H1975-LTC) cells, PC9-EGFR-19del / T790M / C797S (PC9-DTC) cells, A431 cells (EGFR-WT).

[0765] 2. Reagents, consumables and instruments

[0766] 3. Test Methods

[0767] Cells were collected and resuspended in complete culture medium (RPMI 1640 + 10% FBS or DMEM + 15% FBS), counted, and seeded into 96-well plates. The test compounds were added at concentrations of 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, and 0.61 nM, respectively. A control group with cells supplemented with DMSO and a blank control group with cell culture medium were also included. The DMSO concentration was 0.1%. The cell culture plates were incubated at 37°C in a 5% CO2 incubator for 72 hours. After incubation, the cell culture plates were removed, 20 μL of MTT was added to each well, and the plates were incubated at 37°C in a 5% CO2 incubator for 4 hours. The supernatant was discarded, 150 μL of DMSO was added to each well, and the mixture was vortexed. The OD value was measured at 550 nM using a microplate reader. Cell proliferation inhibition rate data were processed using formula (3) to calculate the inhibition rate corresponding to different concentrations of the compound, where OD 化合物 The OD value is the value detected after incubation of the compound. 空白孔 The OD values ​​measured in the cell culture medium wells. OD values ​​were measured in control wells containing DMSO. Inhibition rate curves were plotted using GraphPad Prism software, and IC50 was calculated using SPSS software. 50 value.

[0768]

[0769] Table 4. Inhibitory activity of the compounds of the present invention against the proliferation of different EGFR mutant cells.

[0770] The experimental results show that the compound of the present invention has significant inhibitory activity on the proliferation of H1975-EGFR-L858R / T790M / C797S cells and PC9-EGFR-19del / T790M / C797S cells, but weak inhibitory activity on the proliferation of A431(EGFR-WT) cells, and has good selectivity.

[0771] Experimental Example 3: Mouse Pharmacokinetic Study

[0772] 1. Laboratory animals

[0773] ICR mice, SPF grade, 20-30g. Purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0774] 2. Test Methods

[0775] One day prior to administration, animals were fasted but allowed free access to water for 12 hours. On the day of the experiment, ICR mice were randomly divided into groups of 3 mice each according to their body weight, and the compound was administered by gavage at 10 mpk or intravenously at 1 mpk.

[0776] Sample collection: In the intravenous injection group, 100 μL of blood was collected from the orbital venous plexus of mice before administration (0), and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration and placed in heparin sodium anticoagulant tubes. In the gavage administration group, 100 μL of blood was collected from the orbital venous plexus of mice before administration (0), and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration and placed in heparin sodium anticoagulant tubes. The plasma was centrifuged and transferred to 1.5 mL centrifuge tubes and stored at -80°C. The drug concentration in the plasma was determined by LC-MS / MS.

[0777] Table 5. Pharmacokinetic studies of the compounds of this invention in mice.

[0778] Note: The solvent for the gavage group was 5% DMSO + 5% solubil + 30% PEG400 + 60% (20% HP-β-CD);

[0779] Intravenous group solvent: 5% DMSO + 30% PEG400 + 65% (20% HP-β-CD)

[0780] The experimental results show that the compound of the present invention has good oral absorption in mice.

Claims

1. A compound of formula (I), or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, or deuterated thereof: in, X is CR X Or N; R X Selected from hydrogen, halogen or C 1-3 alkyl; Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy or 5-6-membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl or heteroaryl group is optionally surrounded by one or more carbon atoms. 1-6 Alkyl, C 1-6 Alkyl or halogen atom substitution; R 1 R 2 Each is selected independently from: C 1-6 Alkyl or C 3-6 Cycloalkyl groups, wherein the alkyl group or cycloalkyl group is optionally substituted with 1-5 deuterium or halogen atoms; R 3 Selected from: hydrogen, halogens, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Alkoxy, the C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 The alkoxy group may optionally be replaced by one or more halogens; R 4 Selected from: hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-7 cycloalkyl-O-, the C 1-6 Alkyl, C 1- 6-alkoxy or C 3-7 The cycloalkyl-O- is optionally substituted with one or more halogens; R 5 Selected from: hydrogen, deuterium, halogen, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8-membered heterocyclic, phenyl, or 5-6-membered heteroaryl, wherein the amino, alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, phenyl, or heteroaryl group is optionally surrounded by 1-4 deuterium, halogen, hydroxyl, cyano, or C groups. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 2-6 alkenyl-C(O)- or C 3-6 Cycloalkyl substitution, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms independently selected from O, S, or N; L represents the connecting chain, selected from -L1-L2-L3-L4-L5, where... L1 is selected from 3-12 membered heterocyclic groups or C 3-10 Cycloalkyl groups, wherein the heterocyclic or cycloalkyl group is optionally surrounded by 1 to 4 deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen or C. 1-6 alkyl; L2, L3, L4, and L5 are independently selected from bonds, C, and C, respectively. 1-6 Alkylene, 3-12 membered heterocyclic group, C 3-12 cycloalkyl, C 2-6 imidene group, C 2-6 Ethyne group, -C(O)-, -C(O)-N(R) L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein, the C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally each independently bound by one or more R groups. L3 Replace; the C 1-6 Alkylene, C 2-6 imide and C 2-6 The ethynyl group is optionally and independently controlled by one or more R groups. L4 replace; R L2 Selected from hydrogen or C 1-6 alkyl; Each R L3 Each is independently selected from oxo, hydroxyl, and -OC groups. 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 cycloalkyl, C 1-6 Haloalkyl or 3-12 membered heterocyclic groups; Each R L4 Each is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 cycloalkyl or -OC 1-6 Alkyl; wherein, the C 1-6 Alkyl, C 3-8 cycloalkyl or -OC 1-6 Alkyl groups may be optionally substituted with 1-3 F atoms; LBM is a group that binds to ubiquitin ligases.

2. The compound of claim 1, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterated derivatives, wherein, X is CR X Or N, R X Selected from hydrogen, F, Br, methyl, or ethyl; preferably CH; Z1, Z2, Z3, and Z4 are each independently selected from: N or CR Z The R Z Selected from hydrogen, F, Cl, methyl, ethyl, -CF3-, -CHF2-, cyano or cyclopropyl; preferably: hydrogen, F or methyl; R 1 R 2 Each is independently selected from: methyl, ethyl, isopropyl, or cyclopropyl; preferably: methyl; R 3 Selected from: hydrogen, F, Cl, Br, CF3-, methyl, ethyl, or cyclopropyl; preferably: Br; R 4 Selected from: hydrogen, methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, or CF3CH2-O-; preferably: methoxy or CF3CH2-O-; R 5 Selected from: hydrogen, nitro, CH3C(O)-NH-, methyl, ethyl, vinyl, isopropyl, cyclopropyl, vinyl carbonylamino (CH2=CH2-CONH-), or Preferred: Ethyl or 3. The compound according to any one of claims 1-2, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterates, wherein, LBM is selected from: Each of W1, W2, and W is independently selected from: C(R) b ) or N, the R b Selected from hydrogen or C 1-6 alkyl; Indicates a single bond or a double bond; X1 and Z1 are independently selected from CH or N, and Y1 is selected from CH, N or CO; X2 is selected from: CH2 or C=O; X3 is selected from: CH or N; Y2 is selected from: non-existent, or NR e R e Selected from H or C 1-4 alkyl; R a1 R a2 Each is independently selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl; R c1 Selected from hydrogen, C 1-6 Alkyl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, and 4-6 membered heterocycloalkyl may be optionally substituted with one or more deuterium, halogen, amino, hydroxyl, carboxyl, or cyano groups; R d Selected from hydrogen, halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OC 1-4 alkyl; R d1 Selected from hydrogen or halogen; Preferably, LBM is selected from: More preferably, the LBM is selected from:

4. The compound according to any one of claims 1-3, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterates, wherein, The L is selected from -L1-L2-L3-L4-L5, where, L1 is selected from 4-7 membered monoheterocyclic groups or 7-11 membered heterospirocyclic groups, wherein the monoheterocyclic or heterospirocyclic group is optionally surrounded by one to four deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen, deuterium, or C. 1-3 alkyl; L2, L3, L4, and L5 are independently selected from: key, C 1-6 Alkylene, 4-7 membered monoheterocyclic group, 7-11 membered heterospirocyclic group, 7-9 membered heterobridged cyclic group, C 4-7 cycloalkyl, C 2-6 imidene group, C 2-4 Ethyne group, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R) L2 - or -N(R) L2 -; wherein the monoheterocyclic group, heterospirocyclic group, or heterobridged cyclic group is optionally surrounded by a hydroxyl group, C 1-3 Alkyl or C 1-3 Alkoxy substitution; R L2 Selected from hydrogen or C 1-3 Alkyl groups, wherein the alkyl groups are optionally substituted with 1 to 7 deuterium atoms; Preferably, L1 is selected from a 6-membered monoheterocyclic group or a 7-11-membered heterospirocyclic group, wherein the monoheterocyclic group or heterospirocyclic group is optionally surrounded by one to four deuterium, halogen, hydroxyl, amino, or -OR groups. L1 -N(R) L1 (R) L1’ ) replace, where R L1 R L1’ Each is independently selected from hydrogen, deuterium, or C. 1-3 alkyl; L2, L3, L4, and L5 are independently selected from: key, C 1-6 Alkylene, 4-6 membered monoheterocyclic group, 7-11 membered heterospirocyclic group, 7-9 membered heterobridged cyclic group, C 4-6 cycloalkyl, C 2-4 Ethyne group, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R) L2 - or -N(R) L2 -; wherein the monoheterocyclic group, heterospirocyclic group, or heterobridged cyclic group is optionally surrounded by a hydroxyl group, C 1-3 Alkyl or C 1-3 Alkoxy substitution; R L2 Selected from hydrogen, methyl, or ethyl, wherein the methyl or ethyl group is optionally substituted with 1 to 5 deuterium atoms; More preferably, L1-L2 are selected from: L2, L3, L4 and L5 are each independently selected from: bond, methylene, ethylene, piperidine, piperazine, ethynylene, 1-propynylene, 1-butynylene, -C(O)-, -C(O)-NH-, -C(O)-NCH3-, -NH-, -NCH3-, -NCD3- or 2,5-diazabicyclo[2.2.1]heptane; wherein the piperidine, piperazine or 2,5-diazabicyclo[2.2.1]heptane is optionally substituted with hydroxyl, methoxy or ethoxy.

5. The compound according to any one of claims 1-4, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterates, wherein, The L-LBM is selected from:

6. The compound according to any one of claims 1-5, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterates, wherein, The compound of formula (I) is as follows: Among them, X, Z1, Z2, Z3, Z4, R 1 R 2 R 3 R 4 R 5 L and LBM are as described in the compound of formula (I) above; Preferably, the L-LBM is selected from: More preferably, the LBM is selected from:

7. The compound according to any one of claims 1-6, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, or deuterates, wherein, The compounds of formula (I) are compounds of formulas (I-2), (I-3), (I-4), or (I-5): Among them, X, Z1, Z2, Z3, Z4, R 1 R 2 R 3 R 4 R 5 R c1 As described in compound (I).

8. Of the compounds shown below, or their stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, and deuterated compounds, wherein, The compound is as follows:

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-8, or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, or deuterated thereof, optionally further comprising a pharmaceutically acceptable carrier.

10. Use of the compound of any one of claims 1-8, or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, deuterated compound, or composition of claim 9, in the preparation of a medicament for treating EGFR-mediated diseases.

11. Use of the compound, or stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, deuterated compound, or composition of claim 9, in the preparation of a medicament for treating cancer, preferably EGFR-mediated cancer.

12. Use of the compound of any one of claims 1-8, or a stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate, deuterated compound, or composition of claim 9, in the preparation of a medicament for treating lung cancer, preferably EGFR-mediated lung cancer, wherein the lung cancer is preferably non-small cell lung cancer.

13. The use as described in any one of claims 10-12, wherein, The compound, or its stereoisomers, optical isomers, pharmaceutical salts, prodrugs, solvates, deuterated compounds, or other drugs, may be administered in combination.

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